Brand Name: AVANDIA
Generic Name: rosiglitazone maleate

Contents:

Indications and Usage
Dosage and Administration
Dosage Forms and Strenghts
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
Clinical Studies
How Supplied

Avandia, rosiglitazone maleate, patient information (in plain English)

WARNING

CONGESTIVE HEART FAILURE AND MYOCARDIAL ISCHEMIA

• Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see WARNINGS AND PRECAUTIONS]. After initiation of AVANDIA, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDIA must be considered.
• AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS.]
• A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared AVANDIA to placebo, showed AVANDIA to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients), comparing AVANDIA to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. [See WARNINGS AND PRECAUTIONS.]

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Indications and Usage

Monotherapy and Combination Therapy

AVANDIA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use

• Due to its mechanism of action, AVANDIA is active only in the presence of endogenous insulin. Therefore, AVANDIA should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
• The coadministration of AVANDIA and insulin is not recommended.
• The use of AVANDIA with nitrates is not recommended.

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Dosage and Administration

The management of antidiabetic therapy should be individualized. All patients should start AVANDIA at the lowest recommended dose. Further increases in the dose of AVANDIA should be accompanied by careful monitoring for adverse events related to fluid retention [see Boxed Warning and WARNINGS and PRECAUTIONS].

AVANDIA may be administered at a starting dose of 4 mg either as a single daily dose or in 2 divided doses. For patients who respond inadequately following 8 to 12 weeks of treatment, as determined by reduction in fasting plasma glucose (FPG), the dose may be increased to 8 mg daily as monotherapy or in combination with metformin, sulfonylurea, or sulfonylurea plus metformin. Reductions in glycemic parameters by dose and regimen are described under Clinical Studies . AVANDIA may be taken with or without food.

The total daily dose of AVANDIA should not exceed 8 mg.

Monotherapy

The usual starting dose of AVANDIA is 4 mg administered either as a single dose once daily or in divided doses twice daily. In clinical trials, the 4-mg twice-daily regimen resulted in the greatest reduction in FPG and hemoglobin A1c (HbA1c).

Combination With Sulfonylurea or Metformin

When AVANDIA is added to existing therapy, the current dose(s) of the agent(s) can be continued upon initiation of therapy with AVANDIA.

Sulfonylurea: When used in combination with sulfonylurea, the usual starting dose of AVANDIA is 4 mg administered as either a single dose once daily or in divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

Metformin: The usual starting dose of AVANDIA in combination with metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with AVANDIA.

Combination With Sulfonylurea Plus Metformin

The usual starting dose of AVANDIA in combination with a sulfonylurea plus metformin is 4 mg administered as either a single dose once daily or divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

Specific Patient Populations

Renal Impairment: No dosage adjustment is necessary when AVANDIA is used as monotherapy in patients with renal impairment. Since metformin is contraindicated in such patients, concomitant administration of metformin and AVANDIA is also contraindicated in patients with renal impairment.

Hepatic Impairment: Liver enzymes should be measured prior to initiating treatment with AVANDIA. Therapy with AVANDIA should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal at start of therapy). After initiation of AVANDIA, liver enzymes should be monitored periodically per the clinical judgment of the healthcare professional. [See WARNINGS and PRECAUTIONS and CLINICAL PHARMACOLOGY.]

Pediatric: Data are insufficient to recommend pediatric use of AVANDIA [see USE in SPECIFIC POPULATIONS].

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Dosage forms and Strengths

Pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows:

• 2 mg - pink, debossed with SB on one side and 2 on the other
• 4 mg - orange, debossed with SB on one side and 4 on the other
• 8 mg - red-brown, debossed with SB on one side and 8 on the other

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Contraindications

Initiation of AVANDIA in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see BOXED WARNING].

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Warnings and Precautions

Cardiac Failure

AVANDIA, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered [see BOXED WARNING].

Patients with congestive heart failure (CHF) NYHA Class I and II treated with AVANDIA have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic study was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤ 45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed following treatment with AVANDIA compared to placebo during the 52-week study. (See Table 1.)

Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With AVANDIA or Placebo (in Addition to Background Antidiabetic and CHF Therapy)

Events	AVANDIA N = 110 n (%)	Placebo N = 114 n (%)
Adjudicated
Cardiovascular deaths	5 (5%)	4 (4%)
CHF worsening	7 (6%)	4 (4%)
- with overnight hospitalization	5 (5%)	4 (4%)
- without overnight hospitalization	2 (2%)	0 (0%)
New or worsening edema	28 (25%)	10 (9%)
New or worsening dyspnea	29 (26%)	19 (17%)
Increases in CHF medication	36 (33%)	20 (18%)
Cardiovascular hospitalization*	21 (19%)	15 (13%)
Investigator-reported, non-adjudicated
Ischemic adverse events	10 (9%)	5 (4%)
- Myocardial infarction	5 (5%)	2 (2%)
- Angina	6 (5%)	3 (3%)
* Includes hospitalization for any cardiovascular reason.

Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDIA is not recommended in patients with symptomatic heart failure. [See BOXED WARNING.]

Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of AVANDIA is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDIA during this acute phase should be considered.

Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. AVANDIA is not recommended in patients with NYHA Class III and IV cardiac status.

Myocardial Ischemia

Meta-Analysis of Myocardial Ischemia in a Group of 42 Clinical Trials

A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 42 double-blind, randomized, controlled clinical trials (mean duration 6 months).¹

These studies had been conducted to assess glucose-lowering efficacy in type 2 diabetes, and prospectively planned adjudication of cardiovascular events had not occurred in the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled studies included monotherapy trials (monotherapy with AVANDIA versus placebo monotherapy) and add-on trials (AVANDIA or placebo, added to sulfonylurea, metformin, or insulin). Active control studies included monotherapy trials (monotherapy with AVANDIA versus sulfonylurea or metformin monotherapy) and add-on trials (AVANDIA plus sulfonylurea or AVANDIA plus metformin, versus sulfonylurea plus metformin). A total of 14,237 patients were included (8,604 in treatment groups containing AVANDIA, 5,633 in comparator groups), with 4,143 patient-years of exposure to AVANDIA and 2,675 patient-years of exposure to comparator. Myocardial ischemic events included angina pectoris, angina pectoris aggravated, unstable angina, cardiac arrest, chest pain, coronary artery occlusion, dyspnea, myocardial infarction, coronary thrombosis, myocardial ischemia, coronary artery disease, and coronary artery disorder. In this analysis, an increased risk of myocardial ischemia with AVANDIA versus pooled comparators was observed (2% AVANDIA versus 1.5% comparators, odds ratio 1.4, 95% confidence interval [CI] 1.1, 1.8). An increased risk of myocardial ischemic events with AVANDIA was observed in the placebo-controlled studies, but not in the active-controlled studies. (See Figure 1.)

A greater increased risk of myocardial ischemic events was observed in studies where AVANDIA was added to insulin (2.8% for AVANDIA plus insulin versus 1.4% for placebo plus insulin, [OR 2.1, 95% CI 0.9, 5.1]). This increased risk reflects a difference of 3 events per 100 patient-years (95% CI -0.1, 6.3) between treatment groups. [See WARNINGS AND PRECAUTIONS.]

Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for Myocardial Ischemic Events in the Meta-Analysis of 42 Clinical Trials

A greater increased risk of myocardial ischemia was also observed in patients who received AVANDIA and background nitrate therapy. For AVANDIA (N = 361) versus control (N = 244) in nitrate users, the odds ratio was 2.9 (95% CI 1.4, 5.9), while for non-nitrate users (about 14,000 patients total), the odds ratio was 1.3 (95% CI 0.9, 1.7). This increased risk represents a difference of 12 myocardial ischemic events per 100 patient-years (95% CI 3.3, 21.4). Most of the nitrate users had established coronary heart disease. Among patients with known coronary heart disease who were not on nitrate therapy, an increased risk of myocardial ischemic events for AVANDIA versus comparator was not demonstrated.

Myocardial Ischemic Events in Large Long-Term Prospective Randomized Controlled Trials of AVANDIA

Data from 3 other large, long-term, prospective, randomized, controlled clinical trials of AVANDIA were assessed separately from the meta-analysis. These 3 trials include a total of 14,067 patients (treatment groups containing AVANDIA N = 6,311, comparator groups N = 7,756), with patient-year exposure of 21,803 patient-years for AVANDIA and 25,998 patient-years for comparator. Duration of follow-up exceeded 3 years in each study. ADOPT (A Diabetes Outcomes Progression Trial) was a 4- to 6-year randomized, active-controlled study in recently diagnosed patients with type 2 diabetes naïve to drug therapy.

It was an efficacy and general safety trial that was designed to examine the durability of

AVANDIA as monotherapy (N = 1,456) for glycemic control in type 2 diabetes, with comparator arms of sulfonylurea monotherapy (N = 1,441) and metformin monotherapy (N = 1,454). DREAM (Diabetes Reduction Assessment with Rosiglitazone and Ramipril Medication, published report2) was a 3- to 5-year randomized, placebo-controlled study in patients with impaired glucose tolerance and/or impaired fasting glucose. It had a 2x2 factorial design, intended to evaluate the effect of AVANDIA, and separately of ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes. In DREAM, 2,635 patients were in treatment groups containing AVANDIA, and 2,634 were in treatment groups not containing AVANDIA.Interim results have been published 3 for RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes), an ongoing open-label, 6-year cardiovascular outcomes study in patients with type 2 diabetes with an average treatment duration of 3.75 years. RECORD includes patients who have failed metformin or sulfonylurea monotherapy; those who have failed metformin are randomized to receive either add-on AVANDIA or add-on sulfonylurea, and those who have failed sulfonylurea are randomized to receive either add-on AVANDIA or add-on metformin. In RECORD, a total of 2,220 patients are receiving add-on AVANDIA, and 2,227 patients are on one of the add-on regimens not containing AVANDIA.

For these 3 trials, analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, cardiovascular death, or stroke), referred to hereafter as MACE. This endpoint differed from the meta-analysis' broad endpoint of myocardial ischemic events, more than half of which were angina. Myocardial infarction included adjudicated fatal and nonfatal myocardial infarction plus sudden death. As shown in Figure 2, the results for the 3 endpoints (MACE, MI, and Total Mortality) were not statistically significantly different between AVANDIA and comparators.

In preliminary analyses of the DREAM trial, the incidence of cardiovascular events was higher among subjects who received AVANDIA in combination with ramipril than among subjects who received ramipril alone, as illustrated in Figure 2. This finding was not confirmed in ADOPT and RECORD (active-controlled trials in patients with diabetes) in which 30% and 40% of patients respectively, reported ACE-inhibitor use at baseline.

In their entirety, the available data on the risk of myocardial ischemia are inconclusive. Definitive conclusions regarding this risk await completion of an adequately-designed cardiovascular outcome study.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with AVANDIA or any other oral antidiabetic drug.

Congestive Heart Failure and Myocardial Ischemia During Coadministration of AVANDIA With Insulin

In studies in which AVANDIA was added to insulin, AVANDIA increased the risk of congestive heart failure and myocardial ischemia. (See Table 2.)

Coadministration of AVANDIA and insulin is not recommended. [See Indications and Usage and WARNINGS AND PRECAUTIONS.]

In five, 26-week, controlled, randomized, double-blind trials which were included in the meta-analysis[see WARNINGS AND PRECAUTIONS] , patients with type 2 diabetes mellitus were randomized to coadministration of AVANDIA and insulin (N = 867) or insulin (N = 663). In these 5 trials, AVANDIA was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 21 (2.4%) and 7 (1.1%) in the AVANDIA plus insulin and insulin groups, respectively. The total number of patients with emergent myocardial ischemia was 24 (2.8%) and 9 (1.4%) in the AVANDIA plus insulin and insulin groups, respectively (OR 2.1 [95% CI 0.9, 5.1]). Although the event rate for congestive heart failure and myocardial ischemia was low in the studied population, consistently the event rate was 2-fold or higher with coadministration of AVANDIA and insulin. These cardiovascular events were noted at both the 4 mg and 8 mg daily doses of AVANDIA. (See Table 2.)

Table 2. Occurrence of Cardiovascular Events in 5 Controlled Trials of Addition of AVANDIA to Established Insulin Treatment

Event*	AVANDIA + Insulin (n = 867) n (%)	Insulin (n = 663) n (%)
Congestive heart failure	21 (2.4%)	7 (1.1%)
Myocardial ischemia	24 (2.8%)	9 (1.4%)
Composite of cardiovascular death, myocardial infarction, or stroke	10 (1.2%)	5 (0.8%)
Stroke	5 (0.6%)	4 (0.6%)
Myocardial infarction	4 (0.5%)	1 (0.2%)
Cardiovascular death	4 (0.5%)	1 (0.2%)
All deaths	6 (0.7%)	1 (0.2%)
* Events are not exclusive; i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial ischemia; cardiovascular death, myocardial infarction or stroke; myocardial infarction; cardiovascular death).

In a sixth, 24-week, controlled, randomized, double-blind trial of AVANDIA and insulin coadministration, insulin was added to AVANDAMET® (rosiglitazone maleate and metformin HCl) (n = 161) and compared to insulin plus placebo (n = 158), after a single-blind 8-week run-in with AVANDAMET. Patients with edema requiring pharmacologic therapy and those with congestive heart failure were excluded at baseline and during the run-in period.

In the group receiving AVANDAMET plus insulin, there was one myocardial ischemic event and one sudden death. No myocardial ischemia was observed in the insulin group, and no congestive heart failure was reported in either treatment group.

Edema

AVANDIA should be used with caution in patients with edema. In a clinical study in healthy volunteers who received 8 mg of AVANDIA once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.

Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, AVANDIA should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see BOXED WARNING, WARNINGS AND PRECAUTIONS ].

In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with AVANDIA, and may be dose related. Patients with ongoing edema were more likely to have adverse events associated with edema if started on combination therapy with insulin and AVANDIA [see ADVERSE REACTIONS].

Weight Gain

Dose-related weight gain was seen with AVANDIA alone and in combination with other hypoglycemic agents (Table 3). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see BOXED WARNING].

Table 3. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials

Monotherapy	Duration	Control Group		AVANDIA 4 mg Median (25th, 75th percentile)	AVANDIA 8 mg Median (25th, 75th percentile)
			Median (25th, 75th percentile)
	26 weeks	placebo	-0.9 (-2.8, 0.9) n = 210	1.0 (-0.9, 3.6) n = 436	3.1 (1.1, 5.8) n = 439
	52 weeks	sulfonylurea	2.0 (0, 4.0) n = 173	2.0 (-0.6, 4.0) n = 150	2.6 (0, 5.3) n = 157
Combination therapy
Sulfonylurea	24-26 weeks	sulfonylurea	0 (-1.0, 1.3) n = 1,155	2.2 (0.5, 4.0) n = 613	3.5 (1.4, 5.9) n = 841
Metformin	26 weeks	metformin	-1.4 (-3.2, 0.2) n = 175	0.8 (-1.0, 2.6) n = 100	2.1 (0, 4.3) n = 184
Insulin	26 weeks	insulin	0.9 (-0.5, 2.7) n = 162	4.1 (1.4, 6.3) n = 164	5.4 (3.4, 7.3) n = 150
Sulfonylurea + metformin	26 weeks	sulfonylurea + metformin	0.2 (-1.2, 1.6) n = 272	2.5 (0.8, 4.6) n = 275	4.5 (2.4, 7.3) n = 276

In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication [see Clinical Studies], the median weight change (25^th, 75^th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for AVANDIA, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.

In a 24-week study in pediatric patients aged 10 to 17 years treated with AVANDIA 4 to 8 mg daily, a median weight gain of 2.8 kg (25^th, 75^th percentiles: 0.0, 5.8) was reported.

Hepatic Effects

Liver enzymes should be measured prior to the initiation of therapy with AVANDIA in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with AVANDIA should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤ 2.5X upper limit of normal) at baseline or during therapy with AVANDIA should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDIA in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to > 3X the upper limit of normal in patients on therapy with AVANDIA, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain > 3X the upper limit of normal, therapy with AVANDIA should be discontinued.

If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with AVANDIA should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued. [See ADVERSE REACTIONS.]

Macular Edema

Macular edema has been reported in postmarketing experience in some diabetic patients who were taking AVANDIA or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings. [See ADVERSE REACTIONS.]

Fractures

In a 4- to 6-year comparative study (ADOPT) of glycemic control with monotherapy in drug-naïve patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking AVANDIA. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for AVANDIA versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the study. The majority of the fractures in the women who received AVANDIA occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). No increase in fracture rates was observed in men treated with AVANDIA. The risk of fracture should be considered in the care of patients, especially female patients, treated with AVANDIA, and attention given to assessing and maintaining bone health according to current standards of care.

Hematologic Effects

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with AVANDIA [see ADVERSE REACTIONS]. The observed changes may be related to the increased plasma volume observed with treatment with AVANDIA.

Diabetes and Blood Glucose Control

Patients receiving AVANDIA in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Periodic fasting blood glucose and HbA1c measurements should be performed to monitor therapeutic response.

Ovulation

Therapy with AVANDIA, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking AVANDIA [see Use in Specific Populations]. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies; therefore, the frequency of this occurrence is not known.

Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology], the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDIA should be reviewed.

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Adverse Reactions

Clinical Trial Experience

Adult

In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with AVANDIA.

Short-Term Trials of AVANDIA as Monotherapy and in Combination With Other Hypoglycemic Agents

The incidence and types of adverse events reported in short-term clinical trials of AVANDIA as monotherapy are shown in Table 4.

Table 4. Adverse Events ( ≥ 5% in Any Treatment Group) Reported by Patients in Short-Term*Double-Blind Clinical Trials With AVANDIA as Monotherapy

Preferred Term	AVANDIA Monotherapy N = 2,526 %	Placebo N = 601 %	Metformin N = 225 %	Sulfonylureas† N = 626 %
Upper respiratory tract infection	9.9	8.7	8.9	7.3
Injury	7.6	4.3	7.6	6.1
Headache	5.9	5.0	8.9	5.4
Back pain	4.0	3.8	4.0	5.0
Hyperglycemia	3.9	5.7	4.4	8.1
Fatigue	3.6	5.0	4.0	1.9
Sinusitis	3.2	4.5	5.3	3.0
Diarrhea	2.3	3.3	15.6	3.0
Hypoglycemia	0.6	0.2	1.3	5.9
* Short-term trials ranged from 8 weeks to 1 year. † Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide (N = 21).

Overall, the types of adverse reactions without regard to causality reported when AVANDIA was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with AVANDIA.

Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with AVANDIA.

In double-blind studies, anemia was reported in 1.9% of patients receiving AVANDIA as monotherapy compared to 0.7% on placebo, 0.6% on sulfonylureas, and 2.2% on metformin. Reports of anemia were greater in patients treated with a combination of AVANDIA and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared to monotherapy with AVANDIA or in combination with a sulfonylurea (2.3%). Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anemia in these studies [see ADVERSE REACTIONS].

In clinical trials, edema was reported in 4.8% of patients receiving AVANDIA as monotherapy compared to 1.3% on placebo, 1.0% on sulfonylureas, and 2.2% on metformin. The reporting rate of edema was higher for AVANDIA 8 mg in sulfonylurea combinations (12.4%) compared to other combinations, with the exception of insulin. Edema was reported in 14.7% of patients receiving AVANDIA in the insulin combination trials compared to 5.4% on insulin alone. Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with AVANDIA [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia ( < 1%) and few episodes of hypoglycemia were considered to be severe ( < 1%). Hypoglycemia was the most frequently reported adverse event in the fixed-dose insulin combination trials, although few patients withdrew for hypoglycemia (4 of 408 for AVANDIA plus insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration ≤ 50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with AVANDIA. [See WARNINGS AND PRECAUTIONS.]

Long-Term Trial of AVANDIA as Monotherapy

A 4- to 6-year study (ADOPT) compared the use of AVANDIA (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 5 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to study medication across the 3 treatment groups.

In ADOPT, fractures were reported in a greater number of women treated with AVANDIA (9.3%, 2.7/100 patient-years) compared to glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years).

The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. [See WARNINGS AND PRECAUTIONS.] The observed incidence of fractures for male patients was similar among the 3 treatment groups.

Table 5. On-Therapy Adverse Events ( ≥ 5 Events/100 Patient-Years [PY]) in Any Treatment Group Reported in a 4- to 6-Year Clinical Trial of AVANDIA as Monotherapy (ADOPT)

	AVANDIA N = 1,456 PY = 4,954	Glyburide N = 1,441 PY = 4,244	Metformin N = 1,454 PY = 4,906
Nasopharyngitis	6.3	6.9	6.6
Back pain	5.1	4.9	5.3
Arthralgia	5.0	4.8	4.2
Hypertension	4.4	6.0	6.1
Upper respiratory tract infection	4.3	5.0	4.7
Hypoglycemia	2.9	13.0	3.4
Diarrhea	2.5	3.2	6.8

Pediatric

Avandia has been evaluated for safety in a single, active-controlled trial of pediatric patients with type 2 diabetes in which 99 were treated with Avandia and 101 were treated with metformin. The most common adverse reactions (>10%) without regard to causality for either Avandia or metformin were headache (17% versus 14%), nausea (4% versus 11%), nasopharyngitis (3% versus 12%), and diarrhea (1% versus 13%). In this study, one case of diabetic ketoacidosis was reported in the metformin group. In addition, there were 3 patients in the rosiglitazone group who had FPG of ∼300 mg/dL, 2+ ketonuria, and an elevated anion gap.

Laboratory Abnormalities

Hematologic

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with Avandia (mean decreases in individual studies as much as 1.0 g/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of therapy with Avandia or following a dose increase in Avandia. The time course and magnitude of decreases were similar in patients treated with a combination of Avandia and other hypoglycemic agents or monotherapy with Avandia. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination studies and may have contributed to the higher reporting rate of anemia. In a single study in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with Avandia. White blood cell counts also decreased slightly in adult patients treated with Avandia. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with Avandia.

Lipids

Changes in serum lipids have been observed following treatment with Avandia in adults [see Clinical Pharmacology ]. Small changes in serum lipid parameters were reported in children treated with Avandia for 24 weeks.

Serum Transaminase Levels

In pre-approval clinical studies in 4,598 patients treated with Avandia (3,600 patient-years of exposure) and in a long-term 4- to 6-year study in 1,456 patients treated with Avandia (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with Avandia had elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with Avandia were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with Avandia compared with 0.9% treated with placebo and 1% in patients treated with active comparators. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. [See Warnings and Precautions]

In the 4- to 6-year ADOPT trial, patients treated with Avandia (4,954 patient-years exposure), glyburide (4,244 patient-years exposure), or metformin (4,906 patient-years exposure), as monotherapy, had the same rate of ALT increase to >3X upper limit of normal (0.3 per 100 patient-years exposure).

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of Avandia. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.

In patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported [see Boxed Warning and Warnings and Precautions].

There are postmarketing reports with Avandia of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established.

Rash, pruritus, urticaria, angioedema, anaphylactic reaction, and Stevens-Johnson syndrome have been reported rarely.

Reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received [see Warnings and Precautions].

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Drug Interactions

CYP2C8 Inhibitors and Inducers

An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. [See CLINICAL PHARMACOLOGY.]

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Use in Specific Populations

Pregnancy

Pregnancy Category C.

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Human Data: Rosiglitazone has been reported to cross the human placenta and bedetectable in fetal tissue. The clinical significance of these findings is unknown. There are no adequate and well-controlled studies in pregnant women. AVANDIA should not be used during pregnancy.

Animal Studies: There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose, respectively). Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. For effects on the placenta, embryo/fetus, and offspring, the no-effect dose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately 68 times human AUC at the maximum recommended daily dose). The no-effect level was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth.

Labor and Delivery

The effect of rosiglitazone on labor and delivery in humans is not known.

Nursing Mothers

Drug-related material was detected in milk from lactating rats. It is not known whether AVANDIA is excreted in human milk. Because many drugs are excreted in human milk, AVANDIA should not be administered to a nursing woman.

Pediatric Use

After placebo run-in including diet counseling, children with type 2 diabetes mellitus, aged 10 to 17 years and with a baseline mean body mass index (BMI) of 33 kg/m , were randomized to treatment with 2 mg twice daily of AVANDIA (n = 99) or 500 mg twice daily of metformin (n = 101) in a 24-week, double-blind clinical trial. As expected, FPG decreased in patients naïve to diabetes medication (n = 104) and increased in patients withdrawn from prior medication (usually metformin) (n = 90) during the run-in period. After at least 8 weeks of treatment, 49% of patients treated with AVANDIA and 55% of metformin-treated patients had their dose doubled if FPG >126 mg/dL. For the overall intent-to-treat population, at week 24, the mean change from baseline in HbA1c was -0.14% with AVANDIA and -0.49% with metformin. There was an insufficient number of patients in this study to establish statistically whether these
observed mean treatment effects were similar or different. Treatment effects differed for patients naïve to therapy with antidiabetic drugs and for patients previously treated with antidiabetic therapy (Table 6).

Table 6. Week 24 FPG and HbA1c Change From Baseline Last-Observation-Carried Forward in Children With Baseline HbA1c > 6.5%

	Naïve Patients		Previously-Treated Patients
	Metformin N = 40	Rosiglitazone N = 45	Metformin N = 43	Rosiglitazone N = 32
FPG (mg/dL)
Baseline (mean)	170	165	221	205
Change from baseline (mean)	-21	-11	-33	-5
Adjusted treatment difference* (rosiglitazone-metformin)† (95% CI)		8 (-15, 30)		21 (-9, 51)
% of patients with ≥ 30 mg/dL decrease from baseline	43%	27%	44%	28%
HbA1c (%)
Baseline (mean)	8.3	8.2	8.8	8.5
Change from baseline (mean)	-0.7	-0.5	-0.4	0.1
Adjusted treatment difference* (rosiglitazone-metformin)† (95% CI)		0.2 (-0.6, 0.9)		0.5 (-0.2, 1.3)
% of patients with ≥ 0.7% decrease from baseline	63%	52%	54%	31%
* Change from baseline means are least squares means adjusting for baseline HbA1c, gender, and region. † Positive values for the difference favor metformin.

Treatment differences depended on baseline BMI or weight such that the effects of AVANDIA and metformin appeared more closely comparable among heavier patients. The median weight gain was 2.8 kg with rosiglitazone and 0.2 kg with metformin [see WARNINGS AND PRECAUTIONS]. Fifty-four percent of patients treated with rosiglitazone and 32% of patients treated with metformin gained ≥ 2 kg, and 33% of patients treated with rosiglitazone and 7% of patients treated with metformin gained ≥ 5 kg on study.

Adverse events observed in this study are described in Adverse Reactions).

Figure 3. Mean HbA1c Over Time in a 24-Week Study of AVANDIA and Metformin in Pediatric Patients — Drug-Naïve Subgroup

 

Geriatric Use

Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone [see CLINICAL PHARMACOLOGY]. Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older ( ≥ 65 years) and younger ( < 65 years) patients were observed.

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Overdosage

Limited data are available with regard to overdosage in humans. In clinical studies in volunteers, AVANDIA has been administered at single oral doses of up to 20 mg and was well-tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status.

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Description

AVANDIA (rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. AVANDIA improves glycemic control while reducing circulating insulin levels.

Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors.

Chemically, rosiglitazone maleate is ( ±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The structural formula of rosiglitazone maleate is:

The molecular formula is C18H19N3O3S-C4H4O4. Rosiglitazone maleate is a white to off-white solid with a melting point range of 122 to 123°C. The pKa values of rosiglitazone maleate are 6.8 and 6.1. It is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range.

Each pentagonal film-coated TILTAB tablet contains rosiglitazone maleate equivalent to rosiglitazone, 2 mg, 4 mg, or 8 mg, for oral administration. Inactive ingredients are: Hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin, and 1 or more of the following: Synthetic red and yellow iron oxides and talc.

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Clinical Pharmacology

Mechanism of Action

Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism.

Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker rat.

In animal models, the antidiabetic activity of rosiglitazone was shown to be mediated by increased sensitivity to insulin's action in the liver, muscle, and adipose tissues. Pharmacological studies in animal models indicate that rosiglitazone inhibits hepatic gluconeogenesis. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/or impaired glucose tolerance.

Pharmacodynamics

Patients with lipid abnormalities were not excluded from clinical trials of AVANDIA.

In all 26-week controlled trials, across the recommended dose range, AVANDIA as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. These changes were statistically significantly different from placebo or glyburide controls (Table 7).

Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time. Because of the temporal nature of lipid changes, the 52-week glyburide-controlled study is most pertinent to assess long-term effects on lipids. At baseline, week 26, and week 52, mean LDL/HDL ratios were 3.1, 3.2, and 3.0, respectively, for AVANDIA 4 mg twice daily. The corresponding values for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline between AVANDIA and glyburide at week 52 were statistically significant.

The pattern of LDL and HDL changes following therapy with AVANDIA in combination with other hypoglycemic agents were generally similar to those seen with AVANDIA in monotherapy.

The changes in triglycerides during therapy with AVANDIA were variable and were generally not statistically different from placebo or glyburide controls.

Table 7. Summary of Mean Lipid Changes in 26-Week Placebo-Controlled and 52-Week Glyburide-Controlled Monotherapy Studies

	Placebo-Controlled Studies Week 26			Glyburide-Controlled Study Week 26 and Week 52
	Placebo	AVANDIA		Glyburide Titration		AVANDIA 8 mg
		4 mg daily*	8 mg daily*	Wk 26	Wk 52	Wk 26	Wk 52
Free fatty acids
N	207	428	436	181	168	166	145
Baseline (mean) %	18.1	17.5	17.9	26.4	26.4	26.9	26.6
Change from baseline (mean)	+0.2%	-7.8%	-14.7%	-2.4%	-4.7%	-20.8%	-21.5%
LDL
N	190	400	374	175	160	161	133
Baseline (mean) %	123.7	126.8	125.3	142.7	141.9	142.1	142.1
Change from baseline (mean)	+4.8%	+14.1%	+18.6%	-0.9%	-0.5%	+11.9%	+12.1%
HDL
N	208	429	436	184	170	170	145
Baseline (mean) %	44.1	44.4	43.0	47.2	47.7	48.4	48.3
Change from baseline (mean)	+8.0%	+11.4%	+14.2%	+4.3%	+8.7%	+14.0%	+18.5%
* Once daily and twice daily dosing groups were combined.

Pharmacokinetics

Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range (Table 8). The elimination half-life is 3 to 4 hours and is independent of dose.

Table 8. Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Following Single Oral Doses (N = 32)

Parameter	1 mg Fasting	2 mg Fasting	8 mg Fasting	8 mg Fed
AUC0-inf [ng-hr/mL]	358 (112)	733 (184)	2,971 (730)	2,890 (795)
Cmax [ng/mL]	76 (13)	156 (42)	598 (117)	432 (92)
Half-life [hr]	3.16 (0.72)	3.15 (0.39)	3.37 (0.63)	3.59 (0.70)
CL/F* [L/hr]	3.03 (0.87)	2.89 (0.71)	2.85 (0.69)	2.97 (0.81)
* CL/F = Oral clearance.

Absorption

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, AVANDIA may be administered with or without food.

Distribution

The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily albumin.

Metabolism

Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.

In vitro data demonstrate that rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway.

Excretion

Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [14C]related material ranged from 103 to 158 hours.

Population Pharmacokinetics in Patients With Type 2 Diabetes

Population pharmacokinetic analyses from 3 large clinical trials including 642 men and 405 women with type 2 diabetes (aged 35 to 80 years) showed that the pharmacokinetics of rosiglitazone are not influenced by age, race, smoking, or alcohol consumption. Both oral clearance (CL/F) and oral steady-state volume of distribution (Vss/F) were shown to increase with increases in body weight. Over the weight range observed in these analyses (50 to 150 kg), the range of predicted CL/F and Vss/F values varied by < 1.7-fold and < 2.3-fold, respectively.

Additionally, rosiglitazone CL/F was shown to be influenced by both weight and gender, being lower (about 15%) in female patients.

Special Populations

Geriatric

Results of the population pharmacokinetic analysis (n = 716 < 65 years; n = 331 ≥ 65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone.

Gender

Results of the population pharmacokinetics analysis showed that the mean oral clearance of rosiglitazone in female patients (n = 405) was approximately 6% lower compared to male patients of the same body weight (n = 642).

As monotherapy and in combination with metformin, AVANDIA improved glycemic control in both males and females. In metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response.

In monotherapy studies, a greater therapeutic response was observed in females; however, in more obese patients, gender differences were less evident. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target PPARγ is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to AVANDIA in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone.

Hepatic Impairment

Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared to healthy subjects. As a result, unbound Cmax and AUC0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects.

Therapy with AVANDIA should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT > 2.5X upper limit of normal) at baseline [see WARNINGS AND PRECAUTIONS].

Pediatric

Pharmacokinetic parameters of rosiglitazone in pediatric patients were established using a population pharmacokinetic analysis with sparse data from 96 pediatric patients in a single pediatric clinical trial including 33 males and 63 females with ages ranging from 10 to 17 years (weights ranging from 35 to 178.3 kg). Population mean CL/F and V/F of rosiglitazone were 3.15 L/hr and 13.5 L, respectively. These estimates of CL/F and V/F were consistent with the typical parameter estimates from a prior adult population analysis.

Renal Impairment

There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients compared to subjects with normal renal function. No dosage adjustment is therefore required in such patients receiving AVANDIA. Since metformin is contraindicated in patients with renal impairment, coadministration of metformin with AVANDIA is contraindicated in these patients.

Race

Results of a population pharmacokinetic analysis including subjects of Caucasian, black, and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone.

Drug-Drug Interactions

Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P450

In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, and to a lesser extent, 2C9. AVANDIA (4 mg twice daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethinyl estradiol and norethindrone), which are predominantly metabolized by CYP3A4.

Gemfibrozil

Concomitant administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and rosiglitazone (4 mg once daily) for 7 days increased rosiglitazone AUC by 127%, compared to the administration of rosiglitazone (4 mg once daily) alone. Given the potential for dose-related adverse events with rosiglitazone, a decrease in the dose of rosiglitazone may be needed when gemfibrozil is introduced [see DRUG INTERACTIONS].

Rifampin

Rifampin administration (600 mg once a day), an inducer of CYP2C8, for 6 days is reported to decrease rosiglitazone AUC by 66%, compared to the administration of rosiglitazone (8 mg) alone [see DRUG INTERACTIONS].4

Glyburide

AVANDIA (2 mg twice daily) taken concomitantly with glyburide (3.75 to 10 mg/day) for 7 days did not alter the mean steady-state 24-hour plasma glucose concentrations in diabetic patients stabilized on glyburide therapy. Repeat doses of AVANDIA (8 mg once daily) for 8 days in healthy adult Caucasian subjects caused a decrease in glyburide AUC and Cmax of approximately 30%. In Japanese subjects, glyburide AUC and Cmax slightly increased following coadministration of AVANDIA.

Glimepiride

Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the steady-state pharmacokinetics of AVANDIA. No clinically significant reductions in glimepiride AUC and C_max were observed after repeat doses of AVANDIA (8 mg once daily) for 8 days in healthy adult subjects.

Metformin

Concurrent administration of AVANDIA (2 mg twice daily) and metformin (500 mg twice daily) in healthy volunteers for 4 days had no effect on the steady-state pharmacokinetics of either metformin or rosiglitazone.

Acarbose

Coadministration of acarbose (100 mg three times daily) for 7 days in healthy volunteers had no clinically relevant effect on the pharmacokinetics of a single oral dose of AVANDIA.

Digoxin

Repeat oral dosing of AVANDIA (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers.

Warfarin

Repeat dosing with AVANDIA had no clinically relevant effect on the steady-state pharmacokinetics of warfarin enantiomers.

Ethanol

A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with AVANDIA.

Ranitidine

Pretreatment with ranitidine (150 mg twice daily for 4 days) did not alter the pharmacokinetics of either single oral or intravenous doses of rosiglitazone in healthy volunteers.

These results suggest that the absorption of oral rosiglitazone is not altered in conditions accompanied by increases in gastrointestinal pH.

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Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:

A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively).

Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses 1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses 0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.

Mutagenesis:

Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.

Impairment of Fertility:

Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended human daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis.

Animal Toxicology

Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone treatments (approximately 5, 22, and 2 times human AUC at the maximum recommended human daily dose, respectively). Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion.

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Clinical Studies

Monotherapy

In clinical studies, treatment with AVANDIA resulted in an improvement in glycemic control, as measured by FPG and HbA1c, with a concurrent reduction in insulin and C-peptide. Postprandial glucose and insulin were also reduced. This is consistent with the mechanism of action of AVANDIA as an insulin sensitizer.

The maximum recommended daily dose is 8 mg. Dose-ranging studies suggested that no additional benefit was obtained with a total daily dose of 12 mg.

Short-Term Clinical Studies: A total of 2,315 patients with type 2 diabetes, previously treated with diet alone or antidiabetic medication(s), were treated with AVANDIA as monotherapy in 6 double-blind studies, which included two 26-week placebo-controlled studies, one 52-week glyburide-controlled study, and 3 placebo-controlled dose-ranging studies of 8 to 12 weeks duration. Previous antidiabetic medication(s) were withdrawn and patients entered a 2 to 4 week placebo run-in period prior to randomization.

Two 26-week, double-blind, placebo-controlled trials, in patients with type 2 diabetes (n = 1,401) with inadequate glycemic control (mean baseline FPG approximately 228 mg/dL [101 to 425 mg/dL] and mean baseline HbA1c 8.9% [5.2% to 16.2%]), were conducted. Treatment with AVANDIA produced statistically significant improvements in FPG and HbA1c compared to baseline and relative to placebo. Data from one of these studies are summarized in Table 9.

Table 9: Glycemic Parameters in a 26-Week Placebo-Controlled Trial

	Placebo N = 173	AVANDIA		AVANDIA
		4 mg once daily N = 180	2 mg twice daily N = 186	8 mg once daily N = 181	4 mg twice daily N = 187
FPG (mg/dL)
Baseline (mean)	225	229	225	228	228
Change from baseline (mean)	8	-25	-35	-42	-55
Difference from placebo (adjusted mean)	-	-31*	-43*	-49*	-62*
% of patients with ≥ 30 mg/dL decrease from baseline	19%	45%	54%	58%	70%
HbA1c (%)
Baseline (mean)	8.9	8.9	8.9	8.9	9.0
Change from baseline (mean)	0.8	0.0	-0.1	-0.3	-0.7
Difference from placebo (adjusted mean)	-	-0.8*	-0.9*	-1.1*	-1.5*
% of patients with ≥ 0.7% decrease from baseline	9%	28%	29%	39%	54%
* p < 0.0001 compared to placebo.

When administered at the same total daily dose, AVANDIA was generally more effective in reducing FPG and HbA1c when administered in divided doses twice daily compared to once daily doses. However, for HbA1c, the difference between the 4 mg once daily and 2 mg twice daily doses was not statistically significant.

Long-Term Clinical Studies

Long-term maintenance of effect was evaluated in a 52-week, double-blind, glyburide-controlled trial in patients with type 2 diabetes. Patients were randomized to treatment with AVANDIA 2 mg twice daily (N = 195) or AVANDIA 4 mg twice daily (N = 189) or glyburide (N = 202) for 52 weeks. Patients receiving glyburide were given an initial dosage of either 2.5 mg/day or 5.0 mg/day. The dosage was then titrated in 2.5 mg/day increments over the next 12 weeks, to a maximum dosage of 15.0 mg/day in order to optimize glycemic control. Thereafter, the glyburide dose was kept constant.

The median titrated dose of glyburide was 7.5 mg. All treatments resulted in a statistically significant improvement in glycemic control from baseline (Figure 4 and Figure 5). At the end of week 52, the reduction from baseline in FPG and HbA1c was -40.8 mg/dL and -0.53% with AVANDIA 4 mg twice daily; -25.4 mg/dL and -0.27% with AVANDIA 2 mg twice daily; and -30.0 mg/dL and -0.72% with glyburide. For HbA1c, the difference between AVANDIA 4 mg twice daily and glyburide was not statistically significant at week 52. The initial fall in FPG with glyburide was greater than with AVANDIA; however, this effect was less durable over time.

The improvement in glycemic control seen with AVANDIA 4 mg twice daily at week 26 was maintained through week 52 of the study.

Figure 4. Mean FPG Over Time in a 52-Week Glyburide-Controlled Study

Figure 5. Mean HbA1c Over Time in a 52-Week Glyburide-Controlled Study

Hypoglycemia was reported in 12.1% of glyburide-treated patients versus 0.5% (2 mg twice daily) and 1.6% (4 mg twice daily) of patients treated with AVANDIA. The improvements in glycemic control were associated with a mean weight gain of 1.75 kg and 2.95 kg for patients treated with 2 mg and 4 mg twice daily of AVANDIA, respectively, versus 1.9 kg in glyburide-treated patients. In patients treated with AVANDIA, C-peptide, insulin, pro-insulin, and pro-insulin split products were significantly reduced in a dose-ordered fashion, compared to an increase in the glyburide-treated patients.

A Diabetes Outcome Progression Trial (ADOPT) was a multicenter, double-blind, controlled trial (N = 4,351) conducted over 4 to 6 years to compare the safety and efficacy of AVANDIA, metformin, and glyburide monotherapy in patients recently diagnosed with type 2 diabetes mellitus ( ≤ 3 years) inadequately controlled with diet and exercise. The mean age of patients in this trial was 57 years and the majority of patients (83%) had no known history of cardiovascular disease. The mean baseline FPG and HbA1c were 152 mg/dL and 7.4%, respectively. Patients were randomized to receive either AVANDIA 4 mg once daily, glyburide 2.5 mg once daily, or metformin 500 mg once daily, and doses were titrated to optimal glycemic control up to a maximum of 4 mg twice daily for AVANDIA, 7.5 mg twice daily for glyburide, and 1,000 mg twice daily for metformin. The primary efficacy outcome was time to consecutive FPG > 180 mg/dL after at least 6 weeks of treatment at the maximum tolerated dose of study medication or time to inadequate glycemic control, as determined by an independent adjudication committee.

The cumulative incidence of the primary efficacy outcome at 5 years was 15% with AVANDIA, 21% with metformin, and 34% with glyburide (hazard ratio 0.68 [95% CI 0.55, 0.85] versus metformin, HR 0.37 [95% CI 0.30, 0.45] versus glyburide).

Cardiovascular and adverse event data (including effects on body weight and bone fracture) from ADOPT for AVANDIA, metformin, and glyburide are described in WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, respectively. As with all medications, efficacy results must be considered together with safety information to assess the potential benefit and risk for an individual patient.

Combination With Metformin or Sulfonylurea

The addition of AVANDIA to either metformin or sulfonylurea resulted in significant reductions in hyperglycemia compared to either of these agents alone. These results are consistent with an additive effect on glycemic control when AVANDIA is used as combination therapy.

Combination With Metformin

A total of 670 patients with type 2 diabetes participated in two 26-week, randomized, double-blind, placebo/active-controlled studies designed to assess the efficacy of AVANDIA in combination with metformin. AVANDIA, administered in either once daily or twice daily dosing regimens, was added to the therapy of patients who were inadequately controlled on a maximum dose (2.5 grams/day) of metformin.

In one study, patients inadequately controlled on 2.5 grams/day of metformin (mean baseline FPG 216 mg/dL and mean baseline HbA1c 8.8%) were randomized to receive 4 mg of AVANDIA once daily, 8 mg of AVANDIA once daily, or placebo in addition to metformin. A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of metformin and 4 mg of AVANDIA once daily and 8 mg of AVANDIA once daily, versus patients continued on metformin alone (Table 10).

Table 10. Glycemic Parameters in a 26-Week Combination Study of AVANDIA Plus Metformin

	Metformin N = 113	AVANDIA 4 mg once daily + metformin N = 116	AVANDIA 8 mg once daily + metformin N = 110
FPG (mg/dL)
Baseline (mean)	214	215	220
Change from baseline (mean)	6	-33	-48
Difference from metformin alone (adjusted mean)	-	-40*	-53*
% of patients with ≥ 30 mg/dL decrease from baseline	20%	45%	61%
HbA1c (%)
Baseline (mean)	8.6	8.9	8.9
Change from baseline (mean)	0.5	-0.6	-0.8
Difference from metformin alone (adjusted mean)	-	-1.0*	-1.2*
% of patients with ≥ 0.7% decrease from baseline	11%	45%	52%
* p < 0.0001 compared to metformin.

In a second 26-week study, patients with type 2 diabetes inadequately controlled on 2.5 grams/day of metformin who were randomized to receive the combination of AVANDIA 4 mg twice daily and metformin (N = 105) showed a statistically significant improvement in glycemic control with a mean treatment effect for FPG of -56 mg/dL and a mean treatment effect for HbA1c of -0.8% over metformin alone. The combination of metformin and AVANDIA resulted in lower levels of FPG and HbA1c than either agent alone.

Patients who were inadequately controlled on a maximum dose (2.5 grams/day) of metformin and who were switched to monotherapy with AVANDIA demonstrated loss of glycemic control, as evidenced by increases in FPG and HbA1c. In this group, increases in LDL and VLDL were also seen.

Combination With a Sulfonylurea

A total of 3,457 patients with type 2 diabetes participated in ten 24- to 26-week randomized, double-blind, placebo/active-controlled studies and one 2-year double-blind, active-controlled study in elderly patients designed to assess the efficacy and safety of AVANDIA in combination with a sulfonylurea. AVANDIA 2 mg, 4 mg, or 8 mg daily was administered, either once daily (3 studies) or in divided doses twice daily (7 studies), to patients inadequately controlled on a submaximal or maximal dose of sulfonylurea.

In these studies, the combination of AVANDIA 4 mg or 8 mg daily (administered as single or twice daily divided doses) and a sulfonylurea significantly reduced FPG and HbA1c compared to placebo plus sulfonylurea or further up-titration of the sulfonylurea. Table 11 shows pooled data for 8 studies in which AVANDIA added to sulfonylurea was compared to placebo plus sulfonylurea.

Table 11. Glycemic Parameters in 24- to 26-Week Combination Studies of AVANDIA Plus Sulfonylurea

Twice Daily Divided Dosing (5 Studies)	Sulfonylurea N = 397	AVANDIA 2 mg twice daily + sulfonylurea N = 497	Sulfonylurea N = 248	AVANDIA 4 mg twice daily + sulfonylurea N = 346
FPG (mg/dL)
Baseline (mean)	204	198	188	187
Change from baseline (mean)	11	-29	8	-43
Difference from sulfonylurea alone (adjusted mean)	-	-42*	-	-53*
% of patients with ≥ 30 mg/dL decrease from baseline	17%	49%	15%	61%
HbA1c (%)
Baseline (mean)	9.4	9.5	9.3	9.6
Change from baseline (mean)	0.2	-1.0	0.0	-1.6
Difference from sulfonylurea alone (adjusted mean)	-	-1.1*	-	-1.4*
% of patients with ≥ 0.7% decrease from baseline	21%	60%	23%	75%
Once Daily Dosing(3 Studies)	Sulfonylurea N = 172	AVANDIA 4 mg once daily + sulfonylurea N = 172	Sulfonylurea N = 173	AVANDIA 8 mg once daily + sulfonylurea N = 176
FPG (mg/dL)
Baseline (mean)	198	206	188	192
Change from baseline (mean)	17	-25	17	-43
Difference from sulfonylurea alone (adjusted mean)	-	-47*	-	-66*
% of patients with ≥ 30 mg/dL decrease from baseline	17%	48%	19%	55%
HbA1c (%)
Baseline (mean)	8.6	8.8	8.9	8.9
Change from baseline (mean)	0.4	-0.5	0.1	-1.2
Difference from sulfonylurea alone (adjusted mean)	-	-0.9*	-	-1.4*
% of patients with ≥ 0.7% decrease from baseline	11%	36%	20%	68%
* p < 0.0001 compared to sulfonylurea alone.

One of the 24- to 26-week studies included patients who were inadequately controlled on maximal doses of glyburide and switched to 4 mg of AVANDIA daily as monotherapy; in this group, loss of glycemic control was demonstrated, as evidenced by increases in FPG and HbA1c.

In a 2-year double-blind study, elderly patients (aged 59 to 89 years) on half-maximal sulfonylurea (glipizide 10 mg twice daily) were randomized to the addition of AVANDIA (n = 115, 4 mg once daily to 8 mg as needed) or to continued up-titration of glipizide (n = 110), to a maximum of 20 mg twice daily. Mean baseline FPG and HbA1c were 157 mg/dL and 7.72%, respectively, for the AVANDIA plus glipizide arm and 159 mg/dL and 7.65%, respectively, for the glipizide up-titration arm. Loss of glycemic control (FPG ≥ 180 mg/dL) occurred in a significantly lower proportion of patients (2%) on AVANDIA plus glipizide compared to patients in the glipizide up-titration arm (28.7%). About 78% of the patients on combination therapy completed the 2 years of therapy while only 51% completed on glipizide monotherapy. The effect of combination therapy on FPG and HbA1c was durable over the 2-year study period, with patients achieving a mean of 132 mg/dL for FPG and a mean of 6.98% for HbA1c compared to no change on the glipizide arm.

Combination With Sulfonylurea Plus Metformin

In two 24- to 26-week, double-blind, placebo-controlled, studies designed to assess the efficacy and safety of AVANDIA in combination with sulfonylurea plus metformin, AVANDIA 4 mg or 8 mg daily, was administered in divided doses twice daily, to patients inadequately controlled on submaximal (10 mg) and maximal (20 mg) doses of glyburide and maximal dose of metformin (2 g/day). A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of sulfonylurea plus metformin and 4 mg of AVANDIA and 8 mg of AVANDIA versus patients continued on sulfonylurea plus metformin, as shown in Table 12.

Table 12. Glycemic Parameters in a 26-Week Combination Study of AVANDIA Plus Sulfonylurea and Metformin

	Sulfonylurea + metformin N = 273	AVANDIA 2 mg twice daily + sulfonylurea + metformin N = 276	AVANDIA 4 mg twice daily + sulfonylurea + metformin N = 277
FPG (mg/dL)
Baseline (mean)	189	190	192
Change from baseline (mean)	14	-19	-40
Difference from sulfonylurea plus metformin (adjusted mean)	-	-30*	-52*
% of patients with ≥ 30 mg/dL decrease from baseline	16%	46%	62%
HbA1c (%)
Baseline (mean)	8.7	8.6	8.7
Change from baseline (mean)	0.2	-0.4	-0.9
Difference from sulfonylurea plus metformin (adjusted mean)	-	-0.6*	-1.1*
% of patients with ≥ 0.7% decrease from baseline	16%	39%	63%
* p < 0.0001 compared to placebo.

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References

1. Food and Drug Administration Briefing Document. Joint meeting of the Endocrino Metabolic Drugs and Drug Safety and Risk Management Advisory Committees. Ju 2007.
2. DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in with impaired glucose tolerance or impaired fasting glucose: a randomised controll Lancet 2006;368:1096-1105.
3. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovas outcomes - an interim analysis. NEJM 2007;357:1-11.
4. Park JY, Kim KA, Kang MH, et al. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther 2004;75:157-162.

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How Supplied/Storage and Handling

Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg-pink, debossed with SB on one side and 2 on the other; 4 mg-orange, debossed with SB on one side and 4 on the other; 8 mg-red-brown, debossed with SB on one side and 8 on the other.

• 2 mg bottles of 60: NDC 0029-3158-18
• 4 mg bottles of 30: NDC 0029-3159-13
• 4 mg bottles of 90: NDC 0029-3159-00
• 8 mg bottles of 30: NDC 0029-3160-13
• 8 mg bottles of 90: NDC 0029-3160-59

Store at 25 C (77°F); excursions 15 to 30 C (59 to 86 F). Dispense in a tight, light-resistant container.

last updated 02/2008

Avandia, rosiglitazone maleate, patient information (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

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The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

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Relationship between bipolar disorder and alcohol misuse and abuse, exploring treatment and diagnostic issues.

Inside the Bipolar Disorder and Alcohol Abuse Factsheet

• Introduction
• The relationship between bipolar disorder & alcohol misuse
• Where is bipolar disorder treated?
• Research findings: clinical characteristics
• Diagnostic issues
• Treatments for comorbid bipolar disorder & alcohol misuse

The Mental Health & Alcohol Misuse Project (MHAMP) provides factsheets, a newsletter and web pages aimed at sharing good practice between clinicians and professionals working in the mental health and alcohol fields. MHAMP promotes the inclusion of alcohol in strategies developed for the Mental Health National Service Framework, and updates the mental health and alcohol fields.

Project Factsheet 5:

This factsheet outlines the relationship between bipolar disorder and alcohol misuse, exploring treatment and diagnostic issues. Although bipolar disorder only affects 1-2% of the population, it often requires long-term treatment, which may involve a number of health and social care providers. Importantly, alcohol misuse is high among people with bipolar disorder, and it adversely affects the course of the illness.

Target audience

This factsheet is intended primarily for clinicians and staff working in mental health services, alcohol agencies and primary care. The factsheet may also be of interest to people working in Local Implementation Teams and Primary Care Trusts with an interest in commissioning and planning services to meet the needs of people with comorbid alcohol misuse and bipolar disorder.

Summary: The factsheet at a glance

• People with bipolar disorder are five times more likely to develop alcohol misuse or dependence than the rest of the population
• Comorbid bipolar disorder and alcohol misuse is commonly associated with poor medication compliance, heightened severity of bipolar symptoms, and poor treatment outcomes
• The complex relationship between co-existing alcohol problems and bipolar disorder demonstrates the pressing need to screen for and treat alcohol misuse in this group
• Alcohol misuse can mask diagnostic accuracy in determining the presence of bipolar disorder. Measures that can help determine whether bipolar disorder is present include taking a chronological history of when symptoms developed, considering family history, and observation of mood over extended periods of abstinence
• There are a number of treatment measures that may help those with concurrent alcohol misuse and bipolar disorder. These include screening for alcohol misuse in mental health and primary care settings, screening for mental health problems in primary care and substance misuse agencies and referral to mental health and substance misuse services as required, care planning, patient and carer advice and education, monitoring medication compliance, psychological interventions, and specialist relapse prevention groups.

Introduction

Description

Often called manic depression, bipolar disorder is a type of mood (affective) disorder that affects about 1-2% of the population (Sonne & Brady 2002). People with bipolar disorder experience extreme fluctuations in mood and levels of activity, from euphoria to severe depression, as well as periods of euthymia (normal mood) (Sonne & Brady 2002). Periods of elevated mood and increased energy and activity are called "mania" or "hypomania", while lowered mood and decreased energy and activity is considered "depression" (World Health Organization [WHO] 1992). Bipolar disorder may also include psychotic symptoms, such as hallucinations or delusions (O'Connell 1998).

Classification

Bipolar disorder can be characterised by different manifestations of the illness at different times. The ICD-10 features a range of diagnostic guidelines for various episodes of bipolar disorder: for example, current episode manic with or without psychotic symptoms; current episode severe depression with or without psychotic symptoms (WHO 1992). Bipolar disorders are classified as bipolar I and bipolar II. Bipolar I is the most severe, characterised by manic episodes that last for at least a week and depressive episodes lasting at least two weeks. People can also have symptoms of both depression and mania at the same time (called 'mixed mania'), which may carry a heightened risk of suicide. Bipolar II disorder is characterised by episodes of hypomania, a less severe form of mania, which lasts for at least four consecutive days. Hypomania is interspersed with depressive episodes that last for at least 14 days. Due to elevated mood and inflated self-esteem, people with bipolar II disorder often enjoy being hypomanic and are more likely to seek treatment during a depressive episode than a manic period (Sonne & Brady 2002). Other affective disorders include cyclothymia, characterised by persistent instability of mood, with frequent periods of mild depression and mild elation (WHO 1992).

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As with many other mental illnesses, a significant proportion of people with bipolar disorder misuse alcohol, often complicating their condition. The American Epidemiologic Catchment Area study reported the following findings in relation to bipolar disorders and alcohol:

• 60.7% lifetime prevalence for substance misuse or dependence in persons with bipolar I disorder. Alcohol was the most commonly misused substance, with 46.2% of people with bipolar I disorder experiencing alcohol misuse or dependence at some point in their lives
• The lifetime prevalence of alcohol problems among people with bipolar II disorder was also very high. The likelihood of having bipolar II disorder and any substance misuse or dependence was 48.1%. Again, alcohol was the most commonly misused substance, with 39.2% having either alcohol misuse or dependence at some time in their lives
• For people with any bipolar disorder, the likelihood of having alcohol misuse or dependence is 5.1 times that of the rest of the population-Of the different mental health problems examined in the survey, bipolar I and bipolar II disorders ranked second and third respectively (after antisocial personality disorder) for lifetime prevalence of any alcohol diagnosis (misuse or dependence) (Regier et al. 1990).

 

The relationship between bipolar disorder and alcohol misuse

 

The relationship between alcohol misuse and bipolar disorder is complex and frequently bidirectional (Sonne & Brady 2002). Explanations for the relationship between the two conditions include the following:

• Bipolar disorder may be a risk factor for alcohol misuse (Sonne & Brady 2002)
• Alternatively, the symptoms of bipolar disorder may emerge during chronic alcohol intoxication or during withdrawal (Sonne & Brady 2002)
• People with bipolar disorder may use alcohol during manic episodes in an attempt at "self-medication", either to extend their pleasurable state or to dampen the agitation of mania (Sonne & Brady 2002)
• There is evidence of familial transmission of both alcohol misuse and bipolar disorder, suggesting a family history of bipolar disorder or alcohol misuse can be important risk factors for these conditions (see studies by Merikangas & Gelernter 1990; Preisig et al. 2001, cited in Sonne & Brady 2002)

Alcohol use and withdrawal may affect the same brain chemicals (ie neurotransmitters) involved in bipolar disorder, thereby allowing one disorder to alter the clinical course of the other. In other words, alcohol use or withdrawal may "prompt" the symptoms of bipolar disorder (Tohen et al. 1998, cited in Sonne & Brady 2002).

 

Where is bipolar disorder treated?

 

People with bipolar disorder are frequently treated by GPs and community mental health teams, and in a range of settings, including hospitals, psychiatric wards and psychiatric day hospitals, and special residential care (Gupta & Guest 2002).

Clinicians working with people with comorbid alcohol misuse and bipolar disorder should be competent in the treatment of addictions and bipolar illness. The integrated treatment advocated in the Dual Diagnosis Good Practice Guide entails the concurrent provision of psychiatric and substance misuse interventions, with the same staff member or clinical team working in one setting to provide treatment in a co-ordinated manner (Department of Health [DoH] 2002; see also Mind the Gap, published by the Scottish Executive, 2003). Integrated treatment helps to ensure that both comorbid conditions are treated.

Some dual diagnosis specialist substance misuse services - which include staffing by mental health professionals - also treat clients with comorbid bipolar disorder and alcohol problems (see, for example, MIDAS in East Hertfordshire, reported in Bayney et al. 2002).

Research findings: clinical characteristics

The following section looks at some of the clinical characteristics that the research literature has identified in people with comorbid bipolar disorder and alcohol misuse.

High incidence of comorbidity

As noted previously, of all the different mental health problems considered in the Epidemiologic Catchment Area study, bipolar I and bipolar II disorders ranked second and third for lifetime prevalence of alcohol misuse or dependence (Regier et al. 1990). Other researchers have also found high rates of comorbidity. For example, a study by Winokur et al. (1998) found that alcohol misuse is more frequent among people with bipolar disorder than those with unipolar depression. Therefore, despite the comparatively low incidence of bipolar disorder, the likelihood of alcohol misuse increases markedly with this condition.

Gender

As with the general population, men with bipolar disorder tend to be more likely than women with bipolar disorder to experience alcohol problems. A study by Frye et al. (2003) found that fewer women with bipolar disorder had a lifetime history of alcohol misuse (29.1% of subjects), compared with men with bipolar disorder (49.1%). However, women with bipolar disorder had a much greater likelihood of alcohol misuse compared with the general female population (odds ratio 7.25), than did men with bipolar disorder compared with the general male population (odds ratio 2.77). This suggests that, while men with bipolar disorder are more likely to present with comorbid alcohol misuse than women, bipolar disorder may particularly heighten women's risk of alcohol misuse (when compared to women without the disorder). The study also demonstrates the importance of mental health professionals carefully assessing alcohol use on an ongoing basis among both men and women with bipolar disorder (Frye et al. 2003).

Family history

There may be a link between family history of bipolar illness and alcohol misuse. Research by Winokur et al. (1998) found that, among people with bipolar disorder, familial diathesis (susceptibility) for mania is significantly associated with substance misuse. Family history may be more significant for men than for women. The study by Frye and colleagues (2003) found a stronger relationship between family history of bipolar disorder and alcohol misuse among men with this comorbidity than among women (Frye et al. 2003).

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Other mental health problems

In addition to substance misuse problems, bipolar disorders often co-exist with other mental health problems. A study of patients with bipolar disorder found that 65% had lifetime psychiatric comorbidity for at least one comorbid problem: 42% had comorbid anxiety disorders, 42% substance use disorders, and 5% had eating disorders (McElroy et al. 2001).

Greater severity of symptoms/poorer outcome

Comorbidity of bipolar disorder and substance misuse may be associated with a more adverse onset and course of bipolar disorder. Comorbid conditions are associated with early age at onset of affective symptoms and the bipolar disorder syndrome (McElroy et al. 2001). Compared to bipolar disorder alone, concurrent bipolar disorder and alcohol misuse may lead to more frequent hospitalisations and has been associated with more mixed mania and rapid cycling (four or more mood episodes within 12 months); symptoms considered to increase treatment-resistance (Sonne & Brady 2002). If left untreated, alcohol dependence and withdrawal are likely to worsen mood symptoms, creating an ongoing cycle of alcohol use and mood instability (Sonne & Brady 2002).

Poor medication compliance

There is evidence to suggest that people with comorbid alcohol misuse and bipolar disorder are less likely to be compliant with medication than people with bipolar disorder alone. A study by Keck et al. (1998) followed up bipolar disorder patients discharged from hospital, finding that patients with substance use disorders (including alcohol misuse) were less likely to be fully compliant with pharmacological treatment than patients without substance misuse problems. Importantly, the study also showed that patients with full treatment compliance were more likely to achieve syndromic recovery than those who were noncompliant or only partially compliant. Syndromic recovery was defined as "eight contiguous weeks during which the patient no longer met criteria for a manic, mixed or depressive syndrome" (Keck et al. 1998: 648). Given the relationship of full treatment compliance to syndromic recovery, this study demonstrates the deleterious impact of substance misuse on bipolar disorder, reiterating the pressing need for the treatment of substance misuse.

Suicide risk

Alcohol misuse may increase the risk of suicide among people with bipolar disorder. One study found that 38.4% of their subjects with comorbid bipolar disorder and alcohol misuse make a suicide attempt at some point in their lives, compared to 21.7% of those with bipolar disorder alone (Potash et al. 2000). The authors suggest one possible explanation for the increase in suicide is the "transient disinhibition" caused by alcohol. Potash et al. also found that bipolar disorder, alcohol misuse and attempted suicide cluster in some families, suggesting the possibility of a genetic explanation for these concurrent problems. A non-genetic explanation may be intoxication's "permissive effect" on suicidal behaviour in people with bipolar disorder (Potash et al. 2000).

Diagnostic issues

Determining a correct diagnosis is one of the principal concerns associated with comorbid alcohol misuse and (possible) bipolar disorder. Almost every person with alcohol problems reports mood swings, yet it is important to distinguish these alcohol-induced symptoms from actual bipolar disorder (Sonne & Brady 2002). On the other hand, early recognition of bipolar disorder may help commence appropriate treatment for the condition and lead to decreased vulnerability to alcohol problems (Frye et al. 2003).

Diagnosing bipolar disorder can be difficult because alcohol use and withdrawal, especially with chronic use, can mimic psychiatric disorders (Sonne & Brady 2002). Diagnostic accuracy may also be hampered due to underreporting of symptoms (particularly symptoms of mania), and because of common features shared by both bipolar disorder and alcohol misuse (such as involvement in pleasurable activities with high potential for painful consequences). People with bipolar disorder are also quite likely to misuse drugs other than alcohol (for example, stimulant drugs such as cocaine), which can further confuse the diagnostic process (Shivani et al. 2002). Therefore, it is important to consider whether a person misusing alcohol has an actual bipolar disorder or is merely showing symptoms similar to bipolar disorder.

Making a distinction between primary and secondary disorders can help determine prognosis and treatment: for example, some clients presenting with alcohol problems may have pre-existing bipolar disorder, and could benefit from pharmacological interventions (Schuckit 1979). According to one researcher, primary affective disorder "indicates a persistent change in affect or mood, occurring to the point of interfering with an individual's body and mind functioning" (Schuckit 1979:10). As noted, in people with bipolar disorder, both depression and mania will be observed in the client (Schuckit 1979). Primary alcohol misuse or dependence "implies that the first major life problem related to alcohol occurred in an individual who had no existing psychiatric disorder" (Schuckit 1979: 10). Such problems typically include four areas - legal, occupational, medical and social relationships (Shivani et al. 2002). In considering the relationship between primary and secondary disorders, one approach is to gather information from patients and their families and consider the chronology of when symptoms developed (Schuckit 1979). Medical records are also useful in determining the chronology of symptoms (Shivani et al. 2002).

Alcohol intoxication can produce a syndrome indistinguishable from mania or hypomania, characterised by euphoria, increased energy, decreased appetite, grandiosity, and sometimes paranoia. However, these alcohol-induced manic symptoms generally occur only during active alcohol intoxication - a period of sobriety would make these symptoms easier to differentiate from mania associated with actual bipolar I disorder (Sonne & Brady 2002). Similarly, alcohol-dependent patients undergoing withdrawal may appear to have depression, but studies have shown that depressive symptoms are common in withdrawal, and may persist for two to four weeks following withdrawal (Brown & Schuckit 1988). Observation over lengthier periods of abstinence following withdrawal will help determine a diagnosis of depression (Sonne & Brady 2002).

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Given their more subtle psychiatric symptoms, bipolar II disorder and cyclothymia are even more difficult to diagnose reliably than bipolar I disorder. The researchers Sonne and Brady suggest that it is generally appropriate to diagnose bipolar disorder if bipolar symptoms clearly occur before the onset of alcohol problems or if they persist during periods of sustained abstinence. Family history and the severity of symptoms may also be useful factors in making a diagnosis (Sonne & Brady 2002).

In summary, means to help determine a possible diagnosis of comorbid bipolar disorder include:

• Taking a careful history of the chronology of when symptoms developed
• Considering family and medical history, and severity of symptoms
• Observation of mood over extended periods of abstinence if possible.

Treatments for comorbid bipolar disorder and alcohol misuse

Pharmacological treatments (such as the mood stabilizer lithium) and psychological treatments (such as cognitive therapy and counselling) may work effectively for patients with bipolar disorder alone (O'Connell 1998; Manic Depression Fellowship). Electroconvulsive therapy (ECT) has been effective in treating mania and depression in patients who, for example, are pregnant or unresponsive to standard treatments (Hilty et al. 1999; Fink 2001).

As noted earlier, concurrent alcohol misuse complicates the prognosis and treatment of people with bipolar disorder. However, there is little published information on specific pharmacological and psychotherapeutic treatments for this comorbidity (Sonne & Brady 2002). The following section is not intended as clinical guidance, but as an exploration of treatment considerations for this group.

Screening for alcohol misuse in mental health and primary care settings

Given the significance of alcohol in intensifying the symptoms of psychiatric disorders, clinicians in primary care and mental health services should screen for alcohol misuse when patients present with symptoms of bipolar disorder (Schuckit et al. 1998; Sonne & Brady 2002). A useful tool to gauge alcohol consumption is the World Health Organization's Alcohol Use Disorders Identification Test (AUDIT). Download AUDIT at: http://whqlibdoc.who.int/hq/2001/WHO_MSD_MSB_01.6a.pdf

Referral to mental health services for assessment

Early recognition of bipolar disorder may help commence appropriate treatment for the illness and lead to decreased vulnerability to alcohol problems (Frye et al. 2003). In conjunction with local mental health services, and with suitable training, substance misuse agencies should develop screening tools for mental health problems. This action may help determine whether clients need referral to mental health services for further assessment and treatment.

Treating the addiction and providing education

Given the negative impact of alcohol problems and the benefits of reducing consumption, it is important to treat alcohol problems in people with bipolar disorder. For example, reducing or stopping alcohol intake is recommended in the treatment of rapid cycling in bipolar patients (Kusumakar et al. 1997). In addition, education about the problems associated with alcohol misuse can help clients with pre-existing psychiatric problems (including bipolar disorder) (Schuckit et al. 1997).

Care planning

The Care Programme Approach (CPA) provides a framework for effective mental health care, and comprises:

• Arrangements for assessing the needs of people accepted into mental health services
• The formulation of a care plan that identifies the care required from different providers
• The appointment of a key worker for the service user
• Regular reviews of the care plan (DoH 1999a).

The Mental Health National Service Framework emphasises that the CPA should be applied to people with dual diagnosis, whether they are located in mental health or substance misuse services, beginning with a proper assessment (DoH 2002). A specialist dual diagnosis service in Ayrshire and Arran in Scotland illustrates the use of care planning for people with comorbid mental health and substance misuse problems. At Ayrshire and Arran, care programmes are planned in full consultation with the client, along with a thorough assessment of attendant risk. Care is rarely provided by the dual diagnosis team alone, but in liaison with mainstream services and other organisations relevant to the client's care (Scottish Executive 2003).

Given the complex problems associated with comorbid bipolar disorder and alcohol misuse - such as high suicide risk and poor mediation compliance - it is important that clients with this comorbidity have their care planned and monitored through the CPA. Carers of people on CPA also have the right to an assessment of their needs and to their own written care plan, which should be implemented in consultation with the carer (DoH 1999b).

Medication

Medications frequently used for treating bipolar disorder include the mood stabiliser lithium and a number of anticonvulsants (Geddes & Goodwin 2001). However, these drugs might not be as effective for people with comorbid problems. For example, several studies have reported that substance misuse is a predictor of poor response of bipolar disorder to lithium (Sonne & Brady 2002). As noted, medication compliance can be low among people with bipolar disorder and substance misuse, and the efficacy of medications is frequently being tested (Keck et al. 1998; Kupka et al. 2001; Weiss et al. 1998). For reviews of medications, see Weiss et al. 1998; Geddes & Goodwin 2001; Sonne & Brady 2002.

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Psychological interventions

Psychological interventions such as cognitive therapy may be effective in the treatment of bipolar disorder, possibly as an adjunct to medication (Scott 2001). These interventions can also be useful in treating people with co-existing alcohol problems (Sonne & Brady 2002; Petrakis et al. 2002). Cognitive therapy in patients with bipolar disorder aims "to facilitate acceptance of the disorder and the need for treatment; to help the individual recognise and manage psychosocial stressors and interpersonal problems; to improve medication adherence; to teach strategies to cope with depression and hypomania; to teach early recognition of relapse symptoms and coping techniques; to improve self-management through homework assignments; and to identify and modify negative automatic thoughts, and underlying maladaptive assumptions and beliefs" (Scott 2001: s166). Over a number of sessions, patient and therapist identify and explore problem areas in the patient's life, concluding with a review of the skills and techniques learned (Scott 2001). Cognitive therapy is not the only therapy that can be used for bipolar disorder patients - psychotherapies of proven efficiency in major depressive disorder, such as family therapies, are also being piloted (Scott 2001).

Relapse prevention group

The American researchers Weiss et al. (1999) have developed a manualised relapse prevention group therapy specifically for the treatment of comorbid bipolar disorder and substance misuse. As an integrated programme, the therapy focuses on the treatment of both disorders simultaneously. The group is not considered suitable for patients with acute symptoms of bipolar disorder. Participants must also be seeing a psychiatrist who is prescribing their medication. Weiss et al. are currently evaluating the effectiveness of this therapy.

The major goals of the program are to:

1. "Educate patients about the nature and treatment of their two illnesses
2. Help patients gain further acceptance of their illnesses
3. Help patients offer and receive mutual social support in their effort to recover from their illnesses
4. Help patients desire and attain a goal of abstinence from substances of abuse
5. elp patients comply with the medication regimen and other treatment recommended for their bipolar disorder" (Weiss et al. 1999: 50).

Group therapy comprises 20 hour-long weekly sessions, each covering a specific topic. The group begins with a "check-in", in which participants report their progress towards meeting the treatment goals: saying whether they used alcohol or drugs in the preceding week; the state of their mood during the week; whether they took medications as directed; whether they experienced high risk situations; whether they used any positive coping skills learned in the group; and whether they anticipate any high risk situations in the coming week.

After check-in, the group leader reviews the highlights of the previous week's session and introduces the current group topic. This is followed by an instructive session and a discussion of the current topic. At each meeting, patients receive a session handout summarising the main points. Resources are also available at each session, including information about self-help groups for substance misuse, bipolar disorder and dual diagnosis issues.

Specific session topics cover areas such as:

• The relationship between substance misuse and bipolar disorder
• Instruction on the nature of "triggers"- ie, high-risk situations that might trigger substance misuse, mania and depression
• Reviews on the concepts of depressive thinking and manic thinking
• Experiences with family members and friends
• Recognising early warning signs of relapse to mania, depression and substance misuse
• Alcohol and drug refusal skills
• Using self-help groups for addiction and bipolar disorder
• Taking medication
• Self-care, covering skills for establishing a healthy sleep pattern and HIV risk behaviours
• Developing healthy and supportive relationships (Weiss et al.1999).

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~ all bipolar disorder articles

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References

Bayney, R., St John-Smith, P., and Conhye, A. (2002) 'MIDAS: a new service for the mentally ill with comorbid drug and alcohol misuse', Psychiatric Bulletin 26: 251-254.

Brown, S.A. and Schuckit, M.A. (1988) 'Changes in depression among abstinent alcoholics', Journal of Studies on Alcohol 49 (5): 412-417.

Department of Health (1999a) Effective Care Coordination in Mental Health Services: Modernising the Care Programme Approach, A Policy Booklet (http://www.publications.doh.gov.uk/pub/docs/doh/polbook.pdf)

Department of Health (1999b) A National Service Framework for Mental Health (http://www.dh.gov.uk/en/index.htm)

Department of Health (2002) Mental Health Policy Implementation Guide: Dual diagnosis Good Practice Guide .

Fink, M. (2001) 'Treating bipolar affective disorder', letter, British Medical Journal 322 (7282): 365a.

Frye, M.A. (2003) 'Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder', American Journal of Psychiatry 158 (3): 420-426.

Geddes, J. and Goodwin, G. (2001) 'Bipolar disorder: clinical uncertainty, evidence-based medicine and large-scale randomised trials', British Journal of Psychiatry 178 (suppl. 41): s191-s194.

Gupta, R.D. and Guest, J.F. (2002) 'Annual cost of bipolar disorder to UK society', British Journal of Psychiatry 180: 227-233.

Hilty, D.M., Brady, K.T., and Hales, R.E. (1999) 'A review of bipolar disorder among adults', Psychiatric services 50 (2): 201-213.

Keck, P.E. et al. (1998) '12-month outcome of patients with bipolar disorder following hospitalization for a manic or mixed episode', American Journal of Psychiatry 155 (5): 646-652.

Kupka, R.W. (2001) 'The Stanley Foundation Bipolar Network: 2. Preliminary summary of demographics, course of illness and response to novel treatments', British Journal of Psychiatry 178 (suppl. 41): s177-s183.

Kusumakar, V. et al (1997) 'Treatment of mania, mixed state, and rapid cycling', Canadian Journal of Psychiatry 42 (suppl. 2): 79S-86S.

Manic Depression Fellowship Treatments (http://www.mdf.org.uk/?o=56892)

McElroy, S.L. et al. (2001) 'Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder', American Journal of Psychiatry 158 (3): 420-426.

O'Connell, D.F. (1998) Dual disorders: Essentials for Assessment and Treatment, New York, The Haworth Press.

Petrakis, I.L. et al. (2002) 'Comorbidity of alcoholism and psychiatric disorders: An overview', Alcohol Research & Health26 (2): 81-89.

Potash, J.B. (2000) 'Attempted suicide and alcoholism in bipolar disorder: clinical and familial relationships', American Journal of Psychiatry 157: 2048-2050.

Regier, D.A. et al. (1990) 'Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study', Journal of the American Medical Association 264: 2511-2518.

Schuckit, M.A. (1979) 'Alcoholism and affective disorder: diagnostic confusion', in Goodwin, D.W. and Erickson, C.K. (eds), Alcoholism and Affective Disorders: Clinical, Genetic, and Biochemical Studies, New York, SP Medical & Scientific Books: 9-19.

Schuckit, M.A. et al. (1997) 'The life-time rates of three major mood disorders and four major anxiety disorders in alcoholics and controls', Addiction 92 (10): 1289-1304.

Scott, J. (2001) 'Cognitive therapy as an adjunct to medication in bipolar disorder', British Journal of Psychiatry 178 (suppl. 41): s164-s168.

Scottish Executive (2003) Mind the Gap: Meeting the Needs of People with Co-Occurring Substance and Mental Health Problems (http://www.scotland.gov.uk/library5/health/mtgd.pdf )

Shivani, R., Goldsmith, R.J. and Anthenelli, R.M. (2002) 'Alcoholism and psychiatric disorders: diagnostic challenges', Alcohol Research & Health 26 (2): 90-98.

Sonne, S.C. and Brady, K.T. (2002) 'Bipolar disorder and alcoholism', Alcohol Research and Health 26 (2): 103-108.

Trevisan, L.A. et al. (1998) 'Complications of alcohol withdrawal: pathophysiological insights', Alcohol Health & Research World 22 (1): 61-66.

Weiss, R.D. et al. (1998) 'Medication compliance among patients with bipolar disorder and substance use disorder', Journal of Clinical Psychiatry 59 (4): 172-174.Weiss, R.D. et al. (1999) 'A relapse prevention group for patients with bipolar and substance use disorders', Journal of Substance Abuse Treatment 16 (1): 47-54.

World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines, Geneva, World Health Organization.

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Brand names: Precose
Generic name: Acarbose

Precose, acarbose, full prescribing information

What is Precose and why is Precose prescribed?

Precose is an oral medication used to treat type 2 (noninsulin-dependent) diabetes when high blood sugar levels cannot be controlled by diet alone. Precose works by slowing the body's digestion of carbohydrates so that blood sugar levels won't surge upward after a meal. Precose may be taken alone or in combination with certain other diabetes medications.

Most important fact about Precose

Always remember that Precose is an aid to, not a substitute for, good diet and exercise. Failure to follow the diet and exercise plan recommended by your doctor can lead to serious complications such as dangerously high or low blood sugar levels. If you are overweight, losing pounds and exercising are critically important in controlling your diabetes. Remember, too, that Precose is not an oral form of insulin and cannot be used in place of insulin.

How should you take Precose?

Do not take more or less of Precose than directed by your doctor. Precose is usually taken 3 times a day with the first bite of each main meal.

• If you miss a dose...
  Take it as soon as you remember. If it is almost time for your next dose, skip the one you missed and go back to your regular schedule. Never take 2 doses at the same time. Taking Precose with your 3 main meals will help you to remember your medication schedule.
• Storage instructions...
  Keep the container tightly closed. Protect from temperatures above 77°F. Store away from moisture.

What side effects may occur?

Side effects cannot be anticipated. If any develop or change in intensity, tell your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Precose.

If side effects do occur, they usually appear during the first few weeks of therapy and generally become less intense and less frequent over time. They are rarely severe.

• More common side effects may include:
  Abdominal pain, diarrhea, gas

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Why should Precose not be prescribed?

Do not take Precose when suffering diabetic ketoacidosis (a life-threatening medical emergency caused by insufficient insulin and marked by mental confusion, excessive thirst, nausea, vomiting, headache, fatigue, and a sweet fruity smell to the breath).

You should not take Precose if you have cirrhosis (chronic degenerative liver disease). Also avoid Precose therapy if you have inflammatory bowel disease, ulcers in the colon, any intestinal obstruction or chronic intestinal disease associated with digestion, or any condition that could become worse as a result of gas in the intestine.

Special warnings about Precose

Every 3 months during your first year of treatment, your doctor will give you a blood test to check your liver and see how it is reacting to Precose. While you are taking Precose, you should check your blood and urine periodically for the presence of abnormal sugar (glucose) levels.

Even people with well-controlled diabetes may find that stress such as injury, infection, surgery, or fever results in a loss of control over their blood sugar. If this happens to you, your doctor may recommend that Precose be discontinued temporarily and injected insulin used instead.

When taken alone, Precose does not cause hypoglycemia (low blood sugar), but when you take it in combination with other medications such as Diabinese or Glucotrol, or with insulin, your blood sugar may fall too low. If you have any questions about combining Precose with other medications, be sure to discuss them with your doctor.

If you are taking Precose along with other diabetes medications, be sure to have some source of glucose available in case you experience any symptoms of mild or moderate low blood sugar. (Table sugar won't work because Precose inhibits its absorption.)

• Symptoms of mild hypoglycemia may include:
  Cold sweat, fast heartbeat, fatigue, headache, nausea, and nervousness
• Symptoms of more severe hypoglycemia may include:
  Coma, pale skin, and shallow breathing

Severe hypoglycemia is an emergency. Contact your doctor immediately if the symptoms occur.

Possible food and drug interactions when taking Precose

When you take Precose with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before taking Precose with the following:

• Airway-opening drugs
• Calcium channel blockers (heart and blood pressure medications)
• Charcoal tablets
• Digestive enzyme preparations
• Digoxin
• Estrogens
• Isoniazid
• Major tranquilizers
• Nicotinic acid
• Oral contraceptives
• Phenytoin
• Steroid medications
• Thyroid medications
• Water pills (diuretics)

Special information if you are pregnant or breastfeeding

The effects of Precose during pregnancy have not been adequately studied. If you are pregnant or plan to become pregnant, tell your doctor immediately. Since studies suggest the importance of maintaining normal blood sugar levels during pregnancy, your doctor may prescribe injected insulin. It is not known whether Precose appears in breast milk. Because many drugs do appear in breast milk, you should not take Precose while breastfeeding.

Recommended dosage for Precose

ADULTS

The recommended starting dose of Precose is 25 milligrams (half of a 50-milligram tablet) 3 times a day, taken with the first bite of each main meal. Some people need to work up to this dose gradually and start with 25 milligrams only once a day. Your doctor will adjust your dosage at 4- to 8-week intervals, based on blood tests and your individual response to Precose. The doctor may increase the medication to 50 milligrams 3 times a day or, if needed, 100 milligrams 3 times a day. You should not take more than this amount. If you weigh less than 132 pounds, the maximum dosage is 50 milligrams 3 times a day.

If you are also taking another oral antidiabetic medication or insulin and you show signs of low blood sugar, your doctor will adjust the dosage of both medications.

CHILDREN

Safety and effectiveness of Precose in children have not been established.

Overdosage

An overdose of Precose alone will not cause low blood sugar. However, it may cause a temporary increase in gas, diarrhea, and abdominal discomfort. These symptoms usually disappear quickly. However, in the event of an overdose, do not take any carbohydrate drinks or meals until the symptoms have passed.

last updated 01/2008

Precose, acarbose, full prescribing information

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

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Brand Name: Levemir
Generic Name: Insulin Detemir

Pronounced: IN-su-lin-DE-te-mir

Levemir, insulin detemir, full prescribing information 

What is Levemir and what is it used for?

Levemir is a man-made form of a hormone that is produced in the body. It works by lowering levels of glucose (sugar) in the blood. It is a long-acting form of insulin that is slightly different from other forms of insulin that are not man-made.

Levemir is used to treat diabetes in adults and children.

Levemir may also be used for other purposes not listed in this medication guide.

Important information about Levemir

Many other drugs can potentially interfere with the effects of Levemir. It is extremely important that you tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Levemir is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, overall proper health care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Take care to keep your blood sugar from getting too low, causing hypoglycemia. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, or trouble concentrating. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar. Also be sure your family and close friends know how to help you in an emergency.

Also watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, fruity breath odor, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

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Before using Levemir

You should not use Levemir if you are allergic to insulin, or if you are having an episode of hypoglycemia (low blood sugar). Before using Levemir, tell your doctor if you have kidney or liver disease, or any disorder of your thyroid, adrenal, or pituitary glands.

Tell your doctor about all other medications you use, including any oral (taken by mouth) diabetes medications.

Levemir is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

FDA pregnancy category C. It is not known whether Levemir is harmful to an unborn baby. Before using Levemir, tell your doctor if you are pregnant or plan to become pregnant during treatment It is not known whether insulin detemir passes into breast milk or if it could harm a nursing baby. Do not use Levemir without telling your doctor if you are breast-feeding a baby.

How should I use Levemir?

Use Levemir exactly as it was prescribed for you. Do not use it in larger amounts or for longer than recommended by your doctor. Follow the directions on your prescription label.

Do not mix or dilute Levemir with any other insulin, or use it with an insulin pump.

Levemir is given as an injection (shot) under your skin. Your doctor, nurse, or pharmacist will give you specific instructions on how and where to inject Levemir. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

If you use Levemir once daily, use the injection at your evening meal or at bedtime. If you use Levemir twice daily, use your evening dose at least 12 hours after your morning dose.

Levemir should be thin, clear, and colorless. Do not use the medication if it looks cloudy, has changed colors, or has any particles in it. Call your doctor for a new prescription.

Choose a different place in your injection skin area each time you use Levemir. Do not inject into the same place two times in a row.

If you use an injection pen, attach a new needle to the pen each time you use it. Throw away only the needle in a puncture-proof container. You may continue using the pen for up to 42 days.

Needles may not be included with the injection pen. Ask your doctor or pharmacist which brand and type of needle to use with the pen.

Use each disposable needle only one time. Throw away used needles in a puncture-proof container. If your Levemir does not come with such a container, ask your pharmacist where you can get one. Keep this container out of the reach of children and pets. Your pharmacist can tell you how to properly dispose of the container.

Some insulin needles can be used more than once, depending on needle brand and type. But a reused needle must be properly cleaned, recapped, and inspected for bending or breakage. Reusing needles also increases your risk of infection. Ask your doctor or pharmacist whether you are able to reuse your insulin needles.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Check your blood sugar carefully during a time of stress or illness, if you travel, exercise more than usual, or skip meals. These things can affect your glucose levels and your insulin dose needs may also change.

Watch for signs of blood sugar that is too high (hyperglycemia).

These symptoms include increased thirst, loss of appetite, fruity breath odor, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Ask your doctor how to adjust your Levemir dose if needed. Do not change your dose without first talking to your doctor. Carry an ID card or wear a medical alert bracelet stating that you have diabetes, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you are diabetic.

Storing unopened vials, cartridges, or injection pens: Keep in the carton and store in a refrigerator, protected from light. Throw away any insulin not used before the expiration date on the medicine label. Unopened vials, cartridges, or injection pens may also be stored at room temperature for up to 42 days, away from heat and bright light. Throw away any insulin not used within 42 days. Storing after your first use: Keep the "in-use" vials, cartridges, or injection pens at room temperature and use within 42 days. Do not refrigerate.

Do not freeze Levemir, and throw away the medication if it has become frozen.

What happens if I miss a dose?

Follow your doctor's directions if you miss a dose of insulin.

It is important to keep Levemir on hand at all times. Get your prescription refilled before you run out of medicine completely.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An insulin overdose can cause life-threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, seizure (convulsions), or coma.

What should I avoid while using Levemir?

Do not change the brand of insulin detemir or syringe you are using without first talking to your doctor or pharmacist. Avoid drinking alcohol. Your blood sugar may become dangerously low if you drink alcohol while using Levemir.

Levemir side effects

Get emergency medical help if you have any of these signs of insulin allergy: itching skin rash over the entire body, wheezing, trouble breathing, fast heart rate, sweating, or feeling like you might pass out.

Call your doctor if you have a serious side effect such as:

• swelling in your hands or feet; or
• low potassium (confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling).

Hypoglycemia, or low blood sugar, is the most common side effect of Levemir. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, trouble concentrating, confusion, or seizure (convulsions). Watch for signs of low blood sugar. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar.

Tell your doctor if you have itching, swelling, redness, or thickening of the skin where you inject Levemir.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Levemir?

Using certain medicines can make it harder for you to tell when you have low blood sugar. Tell your doctor if you use any of the following:

• albuterol (Proventil, Ventolin);
• clonidine (Catapres);
• reserpine;
• guanethidine (Ismelin); or
• beta-blockers such as atenolol (Tenormin), bisoprolol (Zebeta), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol(Inderal, InnoPran), timolol (Blocadren), and others.

There are many other medicines that can increase or decrease the effects of Levemir on lowering your blood sugar. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

Where can I get more information?

• Your pharmacist can provide more information about Levemir.
• Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Levemir only for the indication prescribed.

Last Updated 01/2008

Levemir, insulin detemir, full prescribing information

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

back to: Browse all Medications for Diabetes

If a comatose person were to earn an interest of 1 million USD annually on the sum paid to him as compensatory damages - would this be considered an achievement of his? To succeed to earn 1 million USD is universally judged to be an achievement. But to do so while comatose will almost as universally not be counted as one. It would seem that a person has to be both conscious and intelligent to have his achievements qualify.

Even these conditions, though necessary, are not sufficient. If a totally conscious (and reasonably intelligent) person were to accidentally unearth a treasure trove and thus be transformed into a multi-billionaire - his stumbling across a fortune will not qualify as an achievement. A lucky turn of events does not an achievement make. A person must be intent on achieving to have his deeds classified as achievements. Intention is a paramount criterion in the classification of events and actions, as any intensionalist philosopher will tell you.

Supposing a conscious and intelligent person has the intention to achieve a goal. He then engages in a series of absolutely random and unrelated actions, one of which yields the desired result. Will we then say that our person is an achiever?

Not at all. It is not enough to intend. One must proceed to produce a plan of action, which is directly derived from the overriding goal. Such a plan of action must be seen to be reasonable and pragmatic and leading - with great probability - to the achievement. In other words: the plan must involve a prognosis, a prediction, a forecast, which can be either verified or falsified. Attaining an achievement involves the construction of an ad-hoc mini theory. Reality has to be thoroughly surveyed, models constructed, one of them selected (on empirical or aesthetic grounds), a goal formulated, an experiment performed and a negative (failure) or positive (achievement) result obtained. Only if the prediction turns out to be correct can we speak of an achievement.

Our would-be achiever is thus burdened by a series of requirements. He must be conscious, must possess a well-formulated intention, must plan his steps towards the attainment of his goal, and must correctly predict the results of his actions.

But planning alone is not sufficient. One must carry out one's plan of action (from mere plan to actual action). An effort has to be seen to be invested (which must be commensurate with the achievement sought and with the qualities of the achiever). If a person consciously intends to obtain a university degree and constructs a plan of action, which involves bribing the professors into conferring one upon him - this will not be considered an achievement. To qualify as an achievement, a university degree entails a continuous and strenuous effort. Such an effort is commensurate with the desired result. If the person involved is gifted - less effort will be expected of him. The expected effort is modified to reflect the superior qualities of the achiever. Still, an effort, which is deemed to be inordinately or irregularly small (or big!) will annul the standing of the action as an achievement. Moreover, the effort invested must be seen to be continuous, part of an unbroken pattern, bounded and guided by a clearly defined, transparent plan of action and by a declared intention. Otherwise, the effort will be judged to be random, devoid of meaning, haphazard, arbitrary, capricious, etc. - which will erode the achievement status of the results of the actions. This, really, is the crux of the matter: the results are much less important than the coherent, directional, patterns of action. It is the pursuit that matters, the hunt more than the game and the game more than victory or gains. Serendipity cannot underlie an achievement.

These are the internal-epistemological-cognitive determinants as they are translated into action. But whether an event or action is an achievement or not also depends on the world itself, the substrate of the actions.

An achievement must bring about change. Changes occur or are reported to have occurred - as in the acquisition of knowledge or in mental therapy where we have no direct observational access to the events and we have to rely on testimonials. If they do not occur (or are not reported to have occurred) - there would be no meaning to the word achievement. In an entropic, stagnant world - no achievement is ever possible. Moreover: the mere occurrence of change is grossly inadequate. The change must be irreversible or, at least, induce irreversibility, or have irreversible effects. Consider Sisyphus: forever changing his environment (rolling that stone up the mountain slope). He is conscious, is possessed of intention, plans his actions and diligently and consistently carries them out. He is always successful at achieving his goals. Yet, his achievements are reversed by the spiteful gods. He is doomed to forever repeat his actions, thus rendering them meaningless. Meaning is linked to irreversible change, without it, it is not to be found. Sisyphean acts are meaningless and Sisyphus has no achievements to talk about.

Irreversibility is linked not only to meaning, but also to free will and to the lack of coercion or oppression. Sisyphus is not his own master. He is ruled by others. They have the power to reverse the results of his actions and, thus, to annul them altogether. If the fruits of our labour are at the mercy of others - we can never guarantee their irreversibility and, therefore, can never be sure to achieve anything. If we have no free will - we can have no real plans and intentions and if our actions are determined elsewhere - their results are not ours and nothing like achievement exists but in the form of self delusion.

We see that to amply judge the status of our actions and of their results, we must be aware of many incidental things. The context is critical: what were the circumstances, what could have been expected, what are the measures of planning and of intention, of effort and of perseverance which would have "normally" been called for, etc. Labelling a complex of actions and results "an achievement" requires social judgement and social recognition. Take breathing: no one considers this to be an achievement unless Stephen Hawking is involved. Society judges the fact that Hawking is still (mentally and sexually) alert to be an outstanding achievement. The sentence: "an invalid is breathing" would be categorized as an achievement only by informed members of a community and subject to the rules and the ethos of said community. It has no "objective" or ontological weight.

Events and actions are classified as achievements, in other words, as a result of value judgements within given historical, psychological and cultural contexts. Judgement has to be involved: are the actions and their results negative or positive in the said contexts. Genocide, for instance, would have not qualified as an achievement in the USA - but it would have in the ranks of the SS. Perhaps to find a definition of achievement which is independent of social context would be the first achievement to be considered as such anywhere, anytime, by everyone.

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next: Traumas as Social Interactions

Those who believe in the finality of death (i.e., that there is no after-life) - they are the ones who advocate suicide and regard it as a matter of personal choice. On the other hand, those who firmly believe in some form of existence after corporeal death - they condemn suicide and judge it to be a major sin. Yet, rationally, the situation should have been reversed: it should have been easier for someone who believed in continuity after death to terminate this phase of existence on the way to the next. Those who faced void, finality, non-existence, vanishing - should have been greatly deterred by it and should have refrained even from entertaining the idea. Either the latter do not really believe what they profess to believe - or something is wrong with rationality. One would tend to suspect the former.

Suicide is very different from self sacrifice, avoidable martyrdom, engaging in life risking activities, refusal to prolong one's life through medical treatment, euthanasia, overdosing and self inflicted death that is the result of coercion. What is common to all these is the operational mode: a death caused by one's own actions. In all these behaviours, a foreknowledge of the risk of death is present coupled with its acceptance. But all else is so different that they cannot be regarded as belonging to the same class. Suicide is chiefly intended to terminate a life - the other acts are aimed at perpetuating, strengthening and defending values.

Those who commit suicide do so because they firmly believe in the finiteness of life and in the finality of death. They prefer termination to continuation. Yet, all the others, the observers of this phenomenon, are horrified by this preference. They abhor it. This has to do with out understanding of the meaning of life.

Ultimately, life has only meanings that we attribute and ascribe to it. Such a meaning can be external (God's plan) or internal (meaning generated through arbitrary selection of a frame of reference). But, in any case, it must be actively selected, adopted and espoused. The difference is that, in the case of external meanings, we have no way to judge their validity and quality (is God's plan for us a good one or not?). We just "take them on" because they are big, all encompassing and of a good "source". A hyper-goal generated by a superstructural plan tends to lend meaning to our transient goals and structures by endowing them with the gift of eternity. Something eternal is always judged more meaningful than something temporal. If a thing of less or no value acquires value by becoming part of a thing eternal - than the meaning and value reside with the quality of being eternal - not with the thing thus endowed. It is not a question of success. Plans temporal are as successfully implemented as designs eternal. Actually, there is no meaning to the question: is this eternal plan / process / design successful because success is a temporal thing, linked to endeavours that have clear beginnings and ends.

This, therefore, is the first requirement: our life can become meaningful only by integrating into a thing, a process, a being eternal. In other words, continuity (the temporal image of eternity, to paraphrase a great philosopher) is of the essence. Terminating our life at will renders them meaningless. A natural termination of our life is naturally preordained. A natural death is part and parcel of the very eternal process, thing or being which lends meaning to life. To die naturally is to become part of an eternity, a cycle, which goes on forever of life, death and renewal. This cyclic view of life and the creation is inevitable within any thought system, which incorporates a notion of eternity. Because everything is possible given an eternal amount of time - so are resurrection and reincarnation, the afterlife, hell and other beliefs adhered to by the eternal lot.

Sidgwick raised the second requirement and with certain modifications by other philosophers, it reads: to begin to appreciate values and meanings, a consciousness (intelligence) must exist. True, the value or meaning must reside in or pertain to a thing outside the consciousness / intelligence. But, even then, only conscious, intelligent people will be able to appreciate it.

We can fuse the two views: the meaning of life is the consequence of their being part of some eternal goal, plan, process, thing, or being. Whether this holds true or does not - a consciousness is called for in order to appreciate life's meaning. Life is meaningless in the absence of consciousness or intelligence. Suicide flies in the face of both requirements: it is a clear and present demonstration of the transience of life (the negation of the NATURAL eternal cycles or processes). It also eliminates the consciousness and intelligence that could have judged life to have been meaningful had it survived. Actually, this very consciousness / intelligence decides, in the case of suicide, that life has no meaning whatsoever. To a very large extent, the meaning of life is perceived to be a collective matter of conformity. Suicide is a statement, writ in blood, that the community is wrong, that life is meaningless and final (otherwise, the suicide would not have been committed).

This is where life ends and social judgement commences. Society cannot admit that it is against freedom of expression (suicide is, after all, a statement). It never could. It always preferred to cast the suicides in the role of criminals (and, therefore, bereft of any or many civil rights). According to still prevailing views, the suicide violates unwritten contracts with himself, with others (society) and, many might add, with God (or with Nature with a capital N). Thomas Aquinas said that suicide was not only unnatural (organisms strive to survive, not to self annihilate) - but it also adversely affects the community and violates God's property rights. The latter argument is interesting: God is supposed to own the soul and it is a gift (in Jewish writings, a deposit) to the individual. A suicide, therefore, has to do with the abuse or misuse of God's possessions, temporarily lodged in a corporeal mansion.

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This implies that suicide affects the eternal, immutable soul. Aquinas refrains from elaborating exactly how a distinctly physical and material act alters the structure and / or the properties of something as ethereal as the soul. Hundreds of years later, Blackstone, the codifier of British Law, concurred. The state, according to this juridical mind, has a right to prevent and to punish for suicide and for attempted suicide. Suicide is self-murder, he wrote, and, therefore, a grave felony. In certain countries, this still is the case. In Israel, for instance, a soldier is considered to be "army property" and any attempted suicide is severely punished as being "attempt at corrupting army possessions". Indeed, this is paternalism at its worst, the kind that objectifies its subjects. People are treated as possessions in this malignant mutation of benevolence. Such paternalism acts against adults expressing fully informed consent. It is an explicit threat to autonomy, freedom and privacy. Rational, fully competent adults should be spared this form of state intervention. It served as a magnificent tool for the suppression of dissidence in places like Soviet Russia and Nazi Germany. Mostly, it tends to breed "victimless crimes". Gamblers, homosexuals, communists, suicides - the list is long. All have been "protected from themselves" by Big Brothers in disguise. Wherever humans possess a right - there is a correlative obligation not to act in a way that will prevent the exercise of such right, whether actively (preventing it), or passively (reporting it). In many cases, not only is suicide consented to by a competent adult (in full possession of his faculties) - it also increases utility both for the individual involved and for society. The only exception is, of course, where minors or incompetent adults (the mentally retarded, the mentally insane, etc.) are involved. Then a paternalistic obligation seems to exist. I use the cautious term "seems" because life is such a basic and deep set phenomenon that even the incompetents can fully gauge its significance and make "informed" decisions, in my view. In any case, no one is better able to evaluate the quality of life (and the ensuing justifications of a suicide) of a mentally incompetent person - than that person himself.

The paternalists claim that no competent adult will ever decide to commit suicide. No one in "his right mind" will elect this option. This contention is, of course, obliterated both by history and by psychology. But a derivative argument seems to be more forceful. Some people whose suicides were prevented felt very happy that they were. They felt elated to have the gift of life back. Isn't this sufficient a reason to intervene? Absolutely, not. All of us are engaged in making irreversible decisions. For some of these decisions, we are likely to pay very dearly. Is this a reason to stop us from making them? Should the state be allowed to prevent a couple from marrying because of genetic incompatibility? Should an overpopulated country institute forced abortions? Should smoking be banned for the higher risk groups? The answers seem to be clear and negative. There is a double moral standard when it comes to suicide. People are permitted to destroy their lives only in certain prescribed ways.

And if the very notion of suicide is immoral, even criminal - why stop at individuals? Why not apply the same prohibition to political organizations (such as the Yugoslav Federation or the USSR or East Germany or Czechoslovakia, to mention four recent examples)? To groups of people? To institutions, corporations, funds, not for profit organizations, international organizations and so on? This fast deteriorates to the land of absurdities, long inhabited by the opponents of suicide.

 

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next: On Achievement

"Anthropologists report enormous differences in the ways that different cultures categorize emotions. Some languages, in fact, do not even have a word for emotion. Other languages differ in the number of words they have to name emotions. While English has over 2,000 words to describe emotional categories, there are only 750 such descriptive words in Taiwanese Chinese. One tribal language has only 7 words that could be translated into categories of emotion... the words used to name or describe an emotion can influence what emotion is experienced. For example, Tahitians do not have a word directly equivalent to sadness. Instead, they treat sadness as something like a physical illness. This difference has an impact on how the emotion is experienced by Tahitians. For example, the sadness we feel over the departure of a close friend would be experienced by a Tahitian as exhaustion. Some cultures lack words for anxiety or depression or guilt. Samoans have one word encompassing love, sympathy, pity, and liking - which are very different emotions in our own culture."

"Psychology - An Introduction" Ninth Edition By: Charles G. Morris, University of Michigan Prentice Hall, 1996

Introduction

This essay is divided in two parts. In the first, we survey the landscape of the discourse regarding emotions in general and sensations in particular. This part will be familiar to any student of philosophy and can be skipped by same. The second part contains an attempt at producing an integrative overview of the matter, whether successful or not is best left to the reader to judge.

A. Survey

Words have the power to express the speaker's emotions and to evoke emotions (whether the same or not remains disputed) in the listener. Words, therefore, possess emotive meaning together with their descriptive meaning (the latter plays a cognitive role in forming beliefs and understanding).

Our moral judgements and the responses deriving thereof have a strong emotional streak, an emotional aspect and an emotive element. Whether the emotive part predominates as the basis of appraisal is again debatable. Reason analyzes a situation and prescribes alternatives for action. But it is considered to be static, inert, not goal-oriented (one is almost tempted to say: non-teleological). The equally necessary dynamic, action-inducing component is thought, for some oblivious reason, to belong to the emotional realm. Thus, the language (=words) used to express moral judgement supposedly actually express the speaker's emotions. Through the aforementioned mechanism of emotive meaning, similar emotions are evoked in the hearer and he is moved to action.

A distinction should be - and has been - drawn between regarding moral judgement as merely a report pertaining to the subject's inner emotional world - and regarding it wholly as an emotive reaction. In the first case, the whole notion (really, the phenomenon) of moral disagreement is rendered incomprehensible. How could one disagree with a report? In the second case, moral judgement is reduced to the status of an exclamation, a non-propositional expression of "emotive tension", a mental excretion. This absurd was nicknamed: "The Boo-Hoorah Theory".

There were those who maintained that the whole issue was the result of mislabeling. Emotions are really what we otherwise call attitudes, they claimed. We approve or disapprove of something, therefore, we "feel". Prescriptivist accounts displaced emotivist analyses. This instrumentalism did not prove more helpful than its purist predecessors.

Throughout this scholarly debate, philosophers did what they are best at: ignored reality. Moral judgements - every child knows - are not explosive or implosive events, with shattered and scattered emotions strewn all over the battlefield. Logic is definitely involved and so are responses to already analyzed moral properties and circumstances. Moreover, emotions themselves are judged morally (as right or wrong). If a moral judgement were really an emotion, we would need to stipulate the existence of an hyper-emotion to account for the moral judgement of our emotions and, in all likelihood, will find ourselves infinitely regressing. If moral judgement is a report or an exclamation, how are we able to distinguish it from mere rhetoric? How are we able to intelligibly account for the formation of moral standpoints by moral agents in response to an unprecedented moral challenge?

Moral realists criticize these largely superfluous and artificial dichotomies (reason versus feeling, belief versus desire, emotivism and noncognitivism versus realism).

The debate has old roots. Feeling Theories, such as Descartes', regarded emotions as a mental item, which requires no definition or classification. One could not fail to fully grasp it upon having it. This entailed the introduction of introspection as the only way to access our feelings. Introspection not in the limited sense of "awareness of one's mental states" but in the broader sense of "being able to internally ascertain mental states". It almost became material: a "mental eye", a "brain-scan", at the least a kind of perception. Others denied its similarity to sensual perception. They preferred to treat introspection as a modus of memory, recollection through retrospection, as an internal way of ascertaining (past) mental events. This approach relied on the impossibility of having a thought simultaneously with another thought whose subject was the first thought. All these lexicographic storms did not serve either to elucidate the complex issue of introspection or to solve the critical questions: How can we be sure that what we "introspect" is not false? If accessible only to introspection, how do we learn to speak of emotions uniformly? How do we (unreflectively) assume knowledge of other people's emotions? How come we are sometimes forced to "unearth" or deduce our own emotions? How is it possible to mistake our emotions (to have one without actually feeling it)? Are all these failures of the machinery of introspection?

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The proto-psychologists James and Lange have (separately) proposed that emotions are the experiencing of physical responses to external stimuli. They are mental representations of totally corporeal reactions. Sadness is what we call the feeling of crying. This was phenomenological materialism at its worst. To have full-blown emotions (not merely detached observations), one needed to experience palpable bodily symptoms. The James-Lange Theory apparently did not believe that a quadriplegic can have emotions, since he definitely experiences no bodily sensations. Sensationalism, another form of fanatic empiricism, stated that all our knowledge derived from sensations or sense data. There is no clear answer to the question how do these sensa (=sense data) get coupled with interpretations or judgements. Kant postulated the existence of a "manifold of sense" - the data supplied to the mind through sensation. In the "Critique of Pure Reason" he claimed that these data were presented to the mind in accordance with its already preconceived forms (sensibilities, like space and time). But to experience means to unify these data, to cohere them somehow. Even Kant admitted that this is brought about by the synthetic activity of "imagination", as guided by "understanding". Not only was this a deviation from materialism (what material is "imagination" made of?) - it was also not very instructive.

The problem was partly a problem of communication. Emotions are qualia, qualities as they appear to our consciousness. In many respects they are like sense data (which brought about the aforementioned confusion). But, as opposed to sensa, which are particular, qualia are universal. They are subjective qualities of our conscious experience. It is impossible to ascertain or to analyze the subjective components of phenomena in physical, objective terms, communicable and understandable by all rational individuals, independent of their sensory equipment. The subjective dimension is comprehensible only to conscious beings of a certain type (=with the right sensory faculties). The problems of "absent qualia" (can a zombie/a machine pass for a human being despite the fact that it has no experiences) and of "inverted qualia" (what we both call "red" might have been called "green" by you if you had my internal experience when seeing what we call "red") - are irrelevant to this more limited discussion. These problems belong to the realm of "private language". Wittgenstein demonstrated that a language cannot contain elements which it would be logically impossible for anyone but its speaker to learn or understand. Therefore, it cannot have elements (words) whose meaning is the result of representing objects accessible only to the speaker (for instance, his emotions). One can use a language either correctly or incorrectly. The speaker must have at his disposal a decision procedure, which will allow him to decide whether his usage is correct or not. This is not possible with a private language, because it cannot be compared to anything.

In any case, the bodily upset theories propagated by James et al. did not account for lasting or dispositional emotions, where no external stimulus occurred or persisted. They could not explain on what grounds do we judge emotions as appropriate or perverse, justified or not, rational or irrational, realistic or fantastic. If emotions were nothing but involuntary reactions, contingent upon external events, devoid of context - then how come we perceive drug induced anxiety, or intestinal spasms in a detached way, not as we do emotions? Putting the emphasis on sorts of behavior (as the behaviorists do) shifts the focus to the public, shared aspect of emotions but miserably fails to account for their private, pronounced, dimension. It is possible, after all, to experience emotions without expressing them (=without behaving). Additionally, the repertory of emotions available to us is much larger than the repertory of behaviours. Emotions are subtler than actions and cannot be fully conveyed by them. We find even human language an inadequate conduit for these complex phenomena.

To say that emotions are cognitions is to say nothing. We understand cognition even less than we understand emotions (with the exception of the mechanics of cognition). To say that emotions are caused by cognitions or cause cognitions (emotivism) or are part of a motivational process - does not answer the question: "What are emotions?". Emotions do cause us to apprehend and perceive things in a certain way and even to act accordingly. But WHAT are emotions? Granted, there are strong, perhaps necessary, connections between emotions and knowledge and, in this respect, emotions are ways of perceiving the world and interacting with it. Perhaps emotions are even rational strategies of adaptation and survival and not stochastic, isolated inter-psychic events. Perhaps Plato was wrong in saying that emotions conflict with reason and thus obscure the right way of apprehending reality. Perhaps he is right: fears do become phobias, emotions do depend on one's experience and character. As we have it in psychoanalysis, emotions may be reactions to the unconscious rather than to the world. Yet, again, Sartre may be right in saying that emotions are a "modus vivendi", the way we "live" the world, our perceptions coupled with our bodily reactions. He wrote: "(we live the world) as though the relations between things were governed not by deterministic processes but by magic". Even a rationally grounded emotion (fear which generates flight from a source of danger) is really a magical transformation (the ersatz elimination of that source). Emotions sometimes mislead. People may perceive the same, analyze the same, evaluate the situation the same, respond along the same vein - and yet have different emotional reactions. It does not seem necessary (even if it were sufficient) to postulate the existence of "preferred" cognitions - those that enjoy an "overcoat" of emotions. Either all cognitions generate emotions, or none does. But, again, WHAT are emotions?

We all possess some kind of sense awareness, a perception of objects and states of things by sensual means. Even a dumb, deaf and blind person still possesses proprioception (perceiving the position and motion of one's limbs). Sense awareness does not include introspection because the subject of introspection is supposed to be mental, unreal, states. Still, if mental states are a misnomer and really we are dealing with internal, physiological, states, then introspection should form an important part of sense awareness. Specialized organs mediate the impact of external objects upon our senses and distinctive types of experience arise as a result of this mediation.

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Perception is thought to be comprised of the sensory phase - its subjective aspect - and of the conceptual phase. Clearly sensations come before thoughts or beliefs are formed. Suffice it to observe children and animals to be convinced that a sentient being does not necessarily have to have beliefs. One can employ the sense modalities or even have sensory-like phenomena (hunger, thirst, pain, sexual arousal) and, in parallel, engage in introspection because all these have an introspective dimension. It is inevitable: sensations are about how objects feel like, sound, smell and seen to us. The sensations "belong", in one sense, to the objects with which they are identified. But in a deeper, more fundamental sense, they have intrinsic, introspective qualities. This is how we are able to tell them apart. The difference between sensations and propositional attitudes is thus made very clear. Thoughts, beliefs, judgements and knowledge differ only with respect to their content (the proposition believed/judged/known, etc.) and not in their intrinsic quality or feel. Sensations are exactly the opposite: differently felt sensations may relate to the same content. Thoughts can also be classified in terms of intentionality (they are "about" something) - sensations only in terms of their intrinsic character. They are, therefore, distinct from discursive events (such as reasoning, knowing, thinking, or remembering) and do not depend upon the subject's intellectual endowments (like his power to conceptualize). In this sense, they are mentally "primitive" and probably take place at a level of the psyche where reason and thought have no recourse.

The epistemological status of sensations is much less clear. When we see an object, are we aware of a "visual sensation" in addition to being aware of the object? Perhaps we are only aware of the sensation, wherefrom we infer the existence of an object, or otherwise construct it mentally, indirectly? This is what, the Representative Theory tries to persuade us, the brain does upon encountering the visual stimuli emanating from a real, external object. The Naive Realists say that one is only aware of the external object and that it is the sensation that we infer. This is a less tenable theory because it fails to explain how do we directly know the character of the pertinent sensation.

What is indisputable is that sensation is either an experience or a faculty of having experiences. In the first case, we have to introduce the idea of sense data (the objects of the experience) as distinct from the sensation (the experience itself). But isn't this separation artificial at best? Can sense data exist without sensation? Is "sensation" a mere structure of the language, an internal accusative? Is "to have a sensation" equivalent to "to strike a blow" (as some dictionaries of philosophy have it)? Moreover, sensations must be had by subjects. Are sensations objects? Are they properties of the subjects that have them? Must they intrude upon the subject's consciousness in order to exist - or can they exist in the "psychic background" (for instance, when the subject is distracted)? Are they mere representations of real events (is pain a representation of injury)? Are they located? We know of sensations when no external object can be correlated with them or when we deal with the obscure, the diffuse, or the general. Some sensations relate to specific instances - others to kinds of experiences. So, in theory, the same sensation can be experienced by several people. It would be the same KIND of experience - though, of course, different instances of it. Finally, there are the "oddball" sensations, which are neither entirely bodily - nor entirely mental. The sensations of being watched or followed are two examples of sensations with both components clearly intertwined.

Feeling is a "hyper-concept" which is made of both sensation and emotion. It describes the ways in which we experience both our world and our selves. It coincides with sensations whenever it has a bodily component. But it is sufficiently flexible to cover emotions and attitudes or opinions. But attaching names to phenomena never helped in the long run and in the really important matter of understanding them. To identify feelings, let alone to describe them, is not an easy task. It is difficult to distinguish among feelings without resorting to a detailed description of causes, inclinations and dispositions. In addition, the relationship between feeling and emotions is far from clear or well established. Can we emote without feeling? Can we explain emotions, consciousness, even simple pleasure in terms of feeling? Is feeling a practical method, can it be used to learn about the world, or about other people? How do we know about our own feelings?

Instead of throwing light on the subject, the dual concepts of feeling and sensation seem to confound matters even further. A more basic level needs to be broached, that of sense data (or sensa, as in this text).

Sense data are entities cyclically defined. Their existence depends upon being sensed by a sensor equipped with senses. Yet, they define the senses to a large extent (imagine trying to define the sense of vision without visuals). Ostensibly, they are entities, though subjective. Allegedly, they possess the properties that we perceive in an external object (if it is there), as it appears to have them. In other words, though the external object is perceived, what we really get in touch with directly, what we apprehend without mediation - are the subjective sensa. What is (probably) perceived is merely inferred from the sense data. In short, all our empirical knowledge rests upon our acquaintance with sensa. Every perception has as its basis pure experience. But the same can be said about memory, imagination, dreams, hallucinations. Sensation, as opposed to these, is supposed to be error free, not subject to filtering or to interpretation, special, infallible, direct and immediate. It is an awareness of the existence of entities: objects, ideas, impressions, perceptions, even other sensations. Russell and Moore said that sense data have all (and only) the properties that they appear to have and can only be sensed by one subject. But these all are idealistic renditions of senses, sensations and sensa. In practice, it is notoriously difficult to reach a consensus regarding the description of sense data or to base any meaningful (let alone useful) knowledge of the physical world on them. There is a great variance in the conception of sensa. Berkeley, ever the incorrigible practical Briton, said that sense data exist only if and when sensed or perceived by us. Nay, their very existence IS their being perceived or sensed by us. Some sensa are public or part of lager assemblages of sensa. Their interaction with the other sensa, parts of objects, or surfaces of objects may distort the inventory of their properties. They may seem to lack properties that they do possess or to possess properties that can be discovered only upon close inspection (not immediately evident). Some sense data are intrinsically vague. What is a striped pajama? How many stripes does it contain? We do not know. It is sufficient to note (=to visually sense) that it has stripes all over. Some philosophers say that if a sense data can be sensed then they possibly exist. These sensa are called the sensibilia (plural of sensibile). Even when not actually perceived or sensed, objects consist of sensibilia. This makes sense data hard to differentiate. They overlap and where one begins may be the end of another. Nor is it possible to say if sensa are changeable because we do not really know WHAT they are (objects, substances, entities, qualities, events?).

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Other philosophers suggested that sensing is an act directed at the objects called sense data. Other hotly dispute this artificial separation. To see red is simply to see in a certain manner, that is: to see redly. This is the adverbial school. It is close to the contention that sense data are nothing but a linguistic convenience, a noun, which enables us to discuss appearances. For instance, the "Gray" sense data is nothing but a mixture of red and sodium. Yet we use this convention (gray) for convenience and efficacy's sakes.

B. The Evidence

An important facet of emotions is that they can generate and direct behaviour. They can trigger complex chains of actions, not always beneficial to the individual. Yerkes and Dodson observed that the more complex a task is, the more emotional arousal interferes with performance. In other words, emotions can motivate. If this were their only function, we might have determined that emotions are a sub-category of motivations.

Some cultures do not have a word for emotion. Others equate emotions with physical sensations, a-la James-Lange, who said that external stimuli cause bodily changes which result in emotions (or are interpreted as such by the person affected). Cannon and Bard differed only in saying that both emotions and bodily responses were simultaneous. An even more far-fetched approach (Cognitive Theories) was that situations in our environment foster in us a GENERAL state of arousal. We receive clues from the environment as to what we should call this general state. For instance, it was demonstrated that facial expressions can induce emotions, apart from any cognition.

A big part of the problem is that there is no accurate way to verbally communicate emotions. People are either unaware of their feelings or try to falsify their magnitude (minimize or exaggerate them). Facial expressions seem to be both inborn and universal. Children born deaf and blind use them. They must be serving some adaptive survival strategy or function. Darwin said that emotions have an evolutionary history and can be traced across cultures as part of our biological heritage. Maybe so. But the bodily vocabulary is not flexible enough to capture the full range of emotional subtleties humans are capable of. Another nonverbal mode of communication is known as body language: the way we move, the distance we maintain from others (personal or private territory). It expresses emotions, though only very crass and raw ones.

And there is overt behaviour. It is determined by culture, upbringing, personal inclination, temperament and so on. For instance: women are more likely to express emotions than men when they encounter a person in distress. Both sexes, however, experience the same level of physiological arousal in such an encounter. Men and women also label their emotions differently. What men call anger - women call hurt or sadness. Men are four times more likely than women to resort to violence. Women more often than not will internalize aggression and become depressed.

Efforts at reconciling all these data were made in the early eighties. It was hypothesized that the interpretation of emotional states is a two phased process. People respond to emotional arousal by quickly "surveying" and "appraising" (introspectively) their feelings. Then they proceed to search for environmental cues to support the results of their assessment. They will, thus, tend to pay more attention to internal cues that agree with the external ones. Put more plainly: people will feel what they expect to feel.

Several psychologists have shown that feelings precede cognition in infants. Animals also probably react before thinking. Does this mean that the affective system reacts instantaneously, without any of the appraisal and survey processes that were postulated? If this were the case, then we merely play with words: we invent explanations to label our feelings AFTER we fully experience them. Emotions, therefore, can be had without any cognitive intervention. They provoke unlearned bodily patterns, such as the aforementioned facial expressions and body language. This vocabulary of expressions and postures is not even conscious. When information about these reactions reaches the brain, it assigns to them the appropriate emotion. Thus, affect creates emotion and not vice versa.

Sometimes, we hide our emotions in order to preserve our self-image or not to incur society's wrath. Sometimes, we are not aware of our emotions and, as a result, deny or diminish them.

C. An Integrative Platform - A Proposal

(The terminology used in this chapter is explored in the previous ones.)

The use of one word to denote a whole process was the source of misunderstandings and futile disputations. Emotions (feelings) are processes, not events, or objects. Throughout this chapter, I will, therefore, use the term "Emotive Cycle".

The genesis of the Emotive Cycle lies in the acquisition of Emotional Data. In most cases, these are made up of Sense Data mixed with data related to spontaneous internal events. Even when no access to sensa is available, the stream of internally generated data is never interrupted. This is easily demonstrated in experiments involving sensory deprivation or with people who are naturally sensorily deprived (blind, deaf and dumb, for instance). The spontaneous generation of internal data and the emotional reactions to them are always there even in these extreme conditions. It is true that, even under severe sensory deprivation, the emoting person reconstructs or evokes past sensory data. A case of pure, total, and permanent sensory deprivation is nigh impossible. But there are important philosophical and psychological differences between real life sense data and their representations in the mind. Only in grave pathologies is this distinction blurred: in psychotic states, when experiencing phantom pains following the amputation of a limb or in the case of drug induced images and after images. Auditory, visual, olfactory and other hallucinations are breakdowns of normal functioning. Normally, people are well aware of and strongly maintain the difference between objective, external, sense data and the internally generated representations of past sense data.

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The Emotional Data are perceived by the emoter as stimuli. The external, objective component has to be compared to internally maintained databases of previous such stimuli. The internally generated, spontaneous or associative data, have to be reflected upon. Both needs lead to introspective (inwardly directed) activity. The product of introspection is the formation of qualia. This whole process is unconscious or subconscious.

If the person is subject to functioning psychological defense mechanisms (e.g., repression, suppression, denial, projection, projective identification) - qualia formation will be followed by immediate action. The subject - not having had any conscious experience - will not be aware of any connection between his actions and preceding events (sense data, internal data and the introspective phase). He will be at a loss to explain his behaviour, because the whole process did not go through his consciousness. To further strengthen this argument, we may recall that hypnotized and anaesthetized subjects are not likely to act at all even in the presence of external, objective, sensa. Hypnotized people are likely to react to sensa introduced to their consciousness by the hypnotist and which had no existence, whether internal or external, prior to the hypnotist's suggestion. It seems that feeling, sensation and emoting exist only if they pass through consciousness. This is true even where no data of any kind are available (such as in the case of phantom pains in long amputated limbs). But such bypasses of consciousness are the less common cases.

More commonly, qualia formation will be followed by Feeling and Sensation. These will be fully conscious. They will lead to the triple processes of surveying, appraisal/evaluation and judgment formation. When repeated often enough judgments of similar data coalesce to form attitudes and opinions. The patterns of interactions of opinions and attitudes with our thoughts (cognition) and knowledge, within our conscious and unconscious strata, give rise to what we call our personality. These patterns are relatively rigid and are rarely influenced by the outside world. When maladaptive and dysfunctional, we talk about personality disorders.

Judgements contain, therefore strong emotional, cognitive and attitudinal elements which team up to create motivation. The latter leads to action, which both completes one emotional cycle and starts another. Actions are sense data and motivations are internal data, which together form a new chunk of emotional data.

Emotional cycles can be divided to Phrastic nuclei and Neustic clouds (to borrow a metaphor from physics). The Phrastic Nucleus is the content of the emotion, its subject matter. It incorporates the phases of introspection, feeling/sensation, and judgment formation. The Neustic cloud involves the ends of the cycle, which interface with the world: the emotional data, on the one hand and the resulting action on the other.

We started by saying that the Emotional Cycle is set in motion by Emotional Data, which, in turn, are comprised of sense data and internally generated data. But the composition of the Emotional Data is of prime importance in determining the nature of the resulting emotion and of the following action. If more sense data (than internal data) are involved and the component of internal data is weak in comparison (it is never absent) - we are likely to experience Transitive Emotions. The latter are emotions, which involve observation and revolve around objects. In short: these are "out-going" emotions, that motivate us to act to change our environment.

Yet, if the emotional cycle is set in motion by Emotional Data, which are composed mainly of internal, spontaneously generated data - we will end up with Reflexive Emotions. These are emotions that involve reflection and revolve around the self (for instance, autoerotic emotions). It is here that the source of psychopathologies should be sought: in this imbalance between external, objective, sense data and the echoes of our mind.

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next: The Murder of Oneself

Made a list of all persons we had harmed, and became willing to make amends to them all.

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My newfound attitude and direction in life meant that I needed to make a list of the people who had been devastated by my past attitudes and actions.

I reached as far back into my past as I could. I worked to recall all my relationships, beginning with mom and dad, brothers and sisters, grandparents, childhood friends, baby-sitters, kindergarten friends, teachers, church friends, ministers and pastors, neighborhood friends, friends of my parents—any one with whom I had interacted in my formative years, because all these relationships held meaning and keys as to why my adult relationships were going wrong.

Of course, as I reached my teens, I developed more relationships: school friends (and enemies) school teachers, girl friends, class mates, coaches, teammates, principles, etc. And family relationships changed and redefined as I grew older: parents, grandparents, aunts, uncles, and cousins. These had to be re-examined during each phase of my life.

Then came college and marriage: teachers, students, fellow-students, fraternity friends, dorm friends, serious girl friends, mentors, unmarried friends, married friends, and my wife.

Next were in-laws, children, co-workers, employees, employers, more adult friends, older friends from the previous generation, younger friends from subsequent generations, buddies, wife's friends, wife's extended family, in-law's friends, business associates, business mentors, therapists, recovery friends, and God.

The last name I put on the list was my own.

In each of these relationships, my co-dependent behaviors had manifested in one way or another. Usually through being a know-it-all, domineering, my-way-or-the-highway, type of person. I had acted out of my fear-based and shame-based protectiveness. I found some manifestation of my Step Four inventory in each relationship I'd listed. I had indeed hurt others (many others) and myself.

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Some of these people were dead. Some of them I had no way of finding. Some of them didn't want me to find them. I put all their names on the list anyway, because a key to working Step Eight is making the list.

I used the list to discover how I had hurt each relationship, because these were clues to myself and my codependence. These were issues I wanted to overcome. These were issues I wanted to deal with. I wanted to understand the dynamics of these relationships and get past the shame, guilt, despair and turmoil I had helped create in them.

A second key to Step Eight is that I was willing to make the amends.

I was willing to admit the mistakes I'd made. I was willing to change. I was willing to try again. I was willing to discover how to create better relationships, based on healthier premises and boundaries.

Step Eight is as much self-examination as it is relationship examination. Step Eight is about learning who I was and who I am, so that future relationships do not become more emeshed attempts for me to recreate the past and deal with my past yet again in unhealthy ways.

Step Eight is looking at my past, gratefully accepting it, learning from it, and choosing to create healthier relationships in the present.

next: The Twelve Steps of Co-Dependents Anonymous Step Nine

and other Romanticist Mutations

Every type of human activity has a malignant equivalent.

The pursuit of happiness, the accumulation of wealth, the exercise of power, the love of one's self are all tools in the struggle to survive and, as such, are commendable. They do, however, have malignant counterparts: pursuing pleasures (hedonism), greed and avarice as manifested in criminal activities, murderous authoritarian regimes and narcissism.

What separates the malignant versions from the benign ones?

Phenomenologically, they are difficult to tell apart. In which way is a criminal distinct from a business tycoon? Many will say that there is no distinction. Still, society treats the two differently and has set up separate social institutions to accommodate these two human types and their activities.

Is it merely a matter of ethical or philosophical judgement? I think not.

The difference seems to lie in the context. Granted, the criminal and the businessman both have the same motivation (at times, obsession): to make money. Sometimes they both employ the same techniques and adopt the same venues of action. But in which social, moral, philosophical, ethical, historical and biographical contexts do they operate?

A closer examination of their exploits exposes the unbridgeable gap between them. The criminal acts only in the pursuit of money. He has no other considerations, thoughts, motives and emotions, no temporal horizon, no ulterior or external aims, no incorporation of other humans or social institutions in his deliberations. The reverse is true for the businessman. The latter is aware of the fact that he is part of a larger fabric, that he has to obey the law, that some things are not permissible, that sometimes he has to lose sight of moneymaking for the sake of higher values, institutions, or the future. In short: the criminal is a solipsist - the businessman, a socially integrated integrated. The criminal is one track minded - the businessman is aware of the existence of others and of their needs and demands. The criminal has no context - the businessman does ("political animal").

Whenever a human activity, a human institution, or a human thought is refined, purified, reduced to its bare minimum - malignancy ensues. Leukaemia is characterized by the exclusive production of one category of blood cells (the white ones) by the bone marrow - while abandoning the production of others. Malignancy is reductionist: do one thing, do it best, do it more and most, compulsively pursue one course of action, one idea, never mind the costs. Actually, no costs are admitted - because the very existence of a context is denied, or ignored. Costs are brought on by conflict and conflict entails the existence of at least two parties. The criminal does not include in his weltbild the Other. The dictator doesn't suffer because suffering is brought on by recognizing the other (empathy). The malignant forms are sui generis, they are dang am sich, they are categorical, they do not depend on the outside for their existence.

Put differently: the malignant forms are functional but meaningless.

Let us use an illustration to understand this dichotomy:

In France there is a man who made it his life's mission to spit the furthest a human has ever spat. This way he made it into the Guinness Book of Records (GBR). After decades of training, he succeeded to spit to the longest distance a man has ever spat and was included in the GBR under miscellany.

The following can be said about this man with a high degree of certainty:

1. The Frenchman had a purposeful life in the sense that his life had a well-delineated, narrowly focused, and achievable target, which permeated his entire life and defined them.
2. He was a successful man in that he fulfilled his main ambition in life to the fullest. We can rephrase this sentence by saying that he functioned well.
3. He probably was a happy, content, and satisfied man as far as his main theme in life is concerned.
4. He achieved significant outside recognition and affirmation of his achievements.
5. This recognition and affirmation is not limited in time and place

In other words, he became "part of the history".

But how many of us would say that he led a meaningful life? How many would be willing to attribute meaning to his spitting efforts? Not many. His life would look to most of us ridiculous and bereft of meaning.

This judgement is facilitated by comparing his actual history with his potential or possible history. In other words, we derive the sense of meaninglessness partly from comparing his spitting career with what he could have done and achieved had he invested the same time and efforts differently.

He could have raised children, for instance. This is widely considered a more meaningful activity. But why? What makes child rearing more meaningful than distance spitting?

The answer is: common agreement. No philosopher, scientist, or publicist can rigorously establish a hierarchy of the meaningfulness of human actions.

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There are two reasons for this inability:

1. There is no connection between function (functioning, functionality) and meaning (meaninglessness, meaningfulness).
2. There are different interpretations of the word "Meaning" and, yet, people use them interchangeably, obscuring the dialogue.

People often confuse Meaning and Function. When asked what is the meaning of their life they respond by using function-laden phrases. They say: "This activity lends taste (=one interpretation of meaning) to my life", or: "My role in this world is this and, once finished, I will be able to rest in pace, to die". They attach different magnitudes of meaningfulness to various human activities.

Two things are evident:

1. That people use the word "Meaning" not in its philosophically rigorous form. What they mean is really the satisfaction, even the happiness that comes with successful functioning. They want to continue to live when they are flooded by these emotions. They confuse this motivation to live on with the meaning of life. Put differently, they confuse the "why" with the "what for". The philosophical assumption that life has a meaning is a teleological one. Life - regarded linearly as a "progress bar" - proceeds towards something, a final horizon, an aim. But people relate only to what "makes them tick", the pleasure that they derive from being more or less successful in what they set out to do.
2. Either the philosophers are wrong in that they do not distinguish between human activities (from the point of view of their meaningfulness) or people are wrong in that they do. This apparent conflict can be resolved by observing that people and philosophers use different interpretations of the word "Meaning".

To reconcile these antithetical interpretations, it is best to consider three examples:

Assuming there were a religious man who established a new church of which only he was a member.

Would we have said that his life and actions are meaningful?

Probably not.

This seems to imply that quantity somehow bestows meaning. In other words, that meaning is an emergent phenomenon (epiphenomenon). Another right conclusion would be that meaning depends on the context. In the absence of worshippers, even the best run, well-organized, and worthy church might look meaningless. The worshippers - who are part of the church - also provide the context.

This is unfamiliar territory. We are used to associate context with externality. We do not think that our organs provide us with context, for instance (unless we are afflicted by certain mental disturbances). The apparent contradiction is easily resolved: to provide context, the provider of the context provider must be either external - or with the inherent, independent capacity to be so.

The churchgoers do constitute the church - but they are not defined by it, they are external to it and they are not dependent on it. This externality - whether as a trait of the providers of context, or as a feature of an emergent phenomenon - is all-important. The very meaning of the system is derived from it.

A few more examples to support this approach:

Imagine a national hero without a nation, an actor without an audience, and an author without (present or future) readers. Does their work have any meaning? Not really. The external perspective again proves all-important.

There is an added caveat, an added dimension here: time. To deny a work of art any meaning, we must know with total assurance that it will never be seen by anyone. Since this is an impossibility (unless it is to be destroyed) - a work of art has undeniable, intrinsic meaning, a result of the mere potential to be seen by someone, sometime, somewhere. This potential of a " single gaze" is sufficient to endow the work of art with meaning.

To a large extent, the heroes of history, its main characters, are actors with a stage and audience larger than usual. The only difference might be that future audiences often alter the magnitude of their "art": it is either diminished or magnified in the eyes of history.

The third example - originally brought up by Douglas Hofstadter in his magnificent opus "Godel, Escher, Bach - An Eternal Golden Braid" - is genetic material (DNA). Without the right "context" (amino acids) - it has no "meaning" (it does not lead to the production of proteins, the building blocks of the organism encoded in the DNA). To illustrate his point, the author sends DNA on a trip to outer space, where aliens would find it impossible to decipher it (=to understand its meaning).

By now it would seem clear that for a human activity, institution or idea to be meaningful, a context is needed. Whether we can say the same about things natural remains to be seen. Being humans, we tend to assume a privileged status. As in certain metaphysical interpretations of classical quantum mechanics, the observer actively participates in the determination of the world. There would be no meaning if there were no intelligent observers - even if the requirement of context was satisfied (part of the "anthropic principle").

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In other words, not all contexts were created equal. A human observer is needed to determine the meaning, this is an unavoidable constraint. Meaning is the label we give to the interaction between an entity (material or spiritual) and its context (material or spiritual). So, the human observer is forced to evaluate this interaction in order to extract the meaning. But humans are not identical copies, or clones. They are liable to judge the same phenomena differently, dependent upon their vantage point. They are the product of their nature and nurture, the highly specific circumstances of their lives and their idiosyncrasies.

In an age of moral and ethical relativism, a universal hierarchy of contexts is not likely to go down well with the gurus of philosophy. But we are talking about the existence of hierarchies as numerous as the number of observers. This is a notion so intuitive, so embedded in human thinking and behaviour that to ignore it would amount to ignoring reality.

People (observers) have privileged systems of attribution of meaning. They constantly and consistently prefer certain contexts to others in the detection of meaning and the set of its possible interpretations. This set would have been infinite were it not for these preferences. The context preferred, arbitrarily excludes and disallows certain interpretations (and, therefore, certain meanings).

The benign form is, therefore, the acceptance of a plurality of contexts and of the resulting meanings.

The malignant form is to adopt (and, then, impose) a universal hierarchy of contexts with a Master Context which bestows meaning upon everything. Such malignant systems of thought are easily recognizable because they claim to be comprehensive, invariant and universal. In plain language, these thought systems pretend to explain everything, everywhere and in a way not dependent on specific circumstances. Religion is like that and so are most modern ideologies. Science tries to be different and sometimes succeeds. But humans are frail and frightened and they much prefer malignant systems of thinking because they give them the illusion of gaining absolute power through absolute, immutable knowledge.

Two contexts seem to compete for the title of Master Context in human history, the contexts which endow all meanings, permeate all aspects of reality, are universal, invariant, define truth values and solve all moral dilemmas: the Rational and the Affective (emotions).

We live in an age that despite its self-perception as rational is defined and influenced by the emotional Master Context. This is called Romanticism - the malignant form of "being tuned" to one's emotions. It is a reaction to the "cult of idea" which characterized the Enlightenment (Belting, 1998).

Romanticism is the assertion that all human activities are founded on and directed by the individual and his emotions, experience, and mode of expression. As Belting (1998) notes, this gave rise to the concept of the "masterpiece" - an absolute, perfect, unique (idiosyncratic) work by an immediately recognizable and idealized artist.

This relatively novel approach (in historical terms) has permeated human activities as diverse as politics, the formation of families, and art.

Families were once constructed on purely totalitarian bases. Family formation was a transaction, really, involving considerations both financial and genetic. This was substituted (during the 18th century) by love as the main motivation and foundation. Inevitably, this led to the disintegration and to the metamorphosis of the family. To establish a sturdy social institution on such a fickle basis was an experiment doomed to failure.

Romanticism infiltrated the body politic as well. All major political ideologies and movements of the 20th century had romanticist roots, Nazism more than most. Communism touted the ideals of equality and justice while Nazism was a quasi-mythological interpretation of history. Still, both were highly romantic movements.

Politicians were and to a lesser degree today are expected to be extraordinary in their personal lives or in their personality traits. Biographies are recast by image and public relations experts ("spin doctors") to fit this mould. Hitler was, arguably, the most romantic of all world leaders, closely followed by other dictators and authoritarian figures.

It is a cliché to say that, through politicians, we re-enact our relationships with our parents. Politicians are often perceived to be father figures. But Romanticism infantilized this transference. In politicians we want to see not the wise, level headed, ideal father but our actual parents: capriciously unpredictable, overwhelming, powerful, unjust, protecting, and awe-inspiring. This is the romanticist view of leadership: anti-Webberian, anti bureaucratic, chaotic. And this set of predilections, later transformed to social dictates, has had a profound effect on the history of the 20th century.

Romanticism manifested in art through the concept of Inspiration. An artist had to have it in order to create. This led to a conceptual divorce between art and artisanship.

As late as the 18th century, there was no difference between these two classes of creative people, the artists and the artisans. Artists accepted commercial orders which included thematic instructions (the subject, choice of symbols, etc.), delivery dates, prices, etc. Art was a product, almost a commodity, and was treated as such by others (examples: Michelangelo, Leonardo da Vinci, Mozart, Goya, Rembrandt and thousands of artists of similar or lesser stature). The attitude was completely businesslike, creativity was mobilized in the service of the marketplace.

Moreover, artists used conventions - more or less rigid, depending on the period - to express emotions. They traded in emotional expressions where others traded in spices, or engineering skills. But they were all traders and were proud of their artisanship. Their personal lives were subject to gossip, condemnation or admiration but were not considered to be a precondition, an absolutely essential backdrop, to their art.

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The romanticist view of the artist painted him into a corner. His life and art became inextricable. Artists were expected to transmute and transubstantiate their lives as well as the physical materials that they dealt with. Living (the kind of life, which is the subject of legends or fables) became an art form, at times predominantly so.

It is interesting to note the prevalence of romanticist ideas in this context: Weltschmerz, passion, self destruction were considered fit for the artist. A "boring" artist would never sell as much as a "romantically-correct" one. Van Gogh, Kafka and James Dean epitomize this trend: they all died young, lived in misery, endured self-inflicted pains, and ultimate destruction or annihilation. To paraphrase Sontag, their lives became metaphors and they all contracted the metaphorically correct physical and mental illnesses of their day and age: Kafka developed tuberculosis, Van Gogh was mentally ill, James Dean died appropriately in an accident. In an age of social anomies, we tend to appreciate and rate highly the anomalous. Munch and Nietzsche will always be preferable to more ordinary (but perhaps equally creative) people.

Today there is an anti-romantic backlash (divorce, the disintegration of the romantic nation-state, the death of ideologies, the commercialization and popularization of art). But this counter-revolution tackles the external, less substantial facets of Romanticism. Romanticism continues to thrive in the flourishing of mysticism, of ethnic lore, and of celebrity worship. It seems that Romanticism has changed vessels but not its cargo.

We are afraid to face the fact that life is meaningless unless WE observe it, unless WE put it in context, unless WE interpret it. WE feel burdened by this realization, terrified of making the wrong moves, of using the wrong contexts, of making the wrong interpretations.

We understand that there is no constant, unchanged, everlasting meaning to life, and that it all really depends on us. We denigrate this kind of meaning. A meaning that is derived by people from human contexts and experiences is bound to be a very poor approximation to the ONE, TRUE meaning. It is bound to be asymptotic to the Grand Design. It might well be - but this is all we have got and without it our lives will indeed prove meaningless.

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next: The Manifold of Sense

If a lone, unkempt, person, standing on a soapbox were to say that he should become the Prime Minister, he would have been diagnosed by a passing psychiatrist as suffering from this or that mental disturbance. But were the same psychiatrist to frequent the same spot and see a crowd of millions saluting the same lonely, shabby figure - what would have his diagnosis been? Surely, different (perhaps of a more political hue).

It seems that one thing setting social games apart from madness is quantitative: the amount of the participants involved. Madness is a one-person game, and even mass mental disturbances are limited in scope. Moreover, it has long been demonstrated (for instance, by Karen Horney) that the definition of certain mental disorders is highly dependent upon the context of the prevailing culture. Mental disturbances (including psychoses) are time-dependent and locus-dependent. Religious behaviour and romantic behaviour could be easily construed as psychopathologies when examined out of their social, cultural, historical and political contexts.

Historical figures as diverse as Nietzsche (philosophy), Van Gogh (art), Hitler (politics) and Herzl (political visionary) made this smooth phase transition from the lunatic fringes to centre stage. They succeeded to attract, convince and influence a critical human mass, which provided for this transition. They appeared on history's stage (or were placed there posthumously) at the right time and in the right place. The biblical prophets and Jesus are similar examples though of a more severe disorder. Hitler and Herzl possibly suffered from personality disorders - the biblical prophets were, almost certainly, psychotic.

We play games because they are reversible and their outcomes are reversible. No game-player expects his involvement, or his particular moves to make a lasting impression on history, fellow humans, a territory, or a business entity. This, indeed, is the major taxonomic difference: the same class of actions can be classified as "game" when it does not intend to exert a lasting (that is, irreversible) influence on the environment. When such intention is evident - the very same actions qualify as something completely different. Games, therefore, are only mildly associated with memory. They are intended to be forgotten, eroded by time and entropy, by quantum events in our brains and macro-events in physical reality.

Games - as opposed to absolutely all other human activities - are entropic. Negentropy - the act of reducing entropy and increasing order - is present in a game, only to be reversed later. Nowhere is this more evident than in video games: destructive acts constitute the very foundation of these contraptions. When children start to play (and adults, for that matter - see Eric Berne's books on the subject) they commence by dissolution, by being destructively analytic. Playing games is an analytic activity. It is through games that we recognize our temporariness, the looming shadow of death, our forthcoming dissolution, evaporation, annihilation.

These FACTS we repress in normal life - lest they overwhelm us. A frontal recognition of them would render us speechless, motionless, paralysed. We pretend that we are going to live forever, we use this ridiculous, counter-factual assumption as a working hypothesis. Playing games lets us confront all this by engaging in activities which, by their very definition, are temporary, have no past and no future, temporally detached and physically detached. This is as close to death as we get.

Small wonder that rituals (a variant of games) typify religious activities. Religion is among the few human disciplines which tackle death head on, sometimes as a centrepiece (consider the symbolic sacrifice of Jesus). Rituals are also the hallmark of obsessive-compulsive disorders, which are the reaction to the repression of forbidden emotions (our reaction to the prevalence, pervasiveness and inevitability of death is almost identical). It is when we move from a conscious acknowledgement of the relative lack of lasting importance of games - to the pretension that they are important, that we make the transition from the personal to the social.

The way from madness to social rituals traverses games. In this sense, the transition is from game to myth. A mythology is a closed system of thought, which defines the "permissible" questions, those that can be asked. Other questions are forbidden because they cannot be answered without resorting to another mythology altogether.

Observation is an act, which is the anathema of the myth. The observer is presumed to be outside the observed system (a presumption which, in itself, is part of the myth of Science, at least until the Copenhagen Interpretation of Quantum Mechanics was developed).

A game looks very strange, unnecessary and ridiculous from the vantage-point of an outside observer. It has no justification, no future, it looks aimless (from the utilitarian point of view), it can be compared to alternative systems of thought and of social organization (the biggest threat to any mythology). When games are transformed to myths, the first act perpetrated by the group of transformers is to ban all observations by the (willing or unwilling) participants.

Introspection replaces observation and becomes a mechanism of social coercion. The game, in its new guise, becomes a transcendental, postulated, axiomatic and doctrinaire entity. It spins off a caste of interpreters and mediators. It distinguishes participants (formerly, players) from outsiders or aliens (formerly observers or uninterested parties). And the game loses its power to confront us with death. As a myth it assumes the function of repression of this fact and of the fact that we are all prisoners. Earth is really a death ward, a cosmic death row: we are all trapped here and all of us are sentenced to die.

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Today's telecommunications, transportation, international computer networks and the unification of the cultural offering only serve to exacerbate and accentuate this claustrophobia. Granted, in a few millennia, with space travel and space habitation, the walls of our cells will have practically vanished (or become negligible) with the exception of the constraint of our (limited) longevity. Mortality is a blessing in disguise because it motivates humans to act in order "not to miss the train of life" and it maintains the sense of wonder and the (false) sense of unlimited possibilities.

This conversion from madness to game to myth is subjected to meta-laws that are the guidelines of a super-game. All our games are derivatives of this super-game of survival. It is a game because its outcomes are not guaranteed, they are temporary and to a large extent not even known (many of our activities are directed at deciphering it). It is a myth because it effectively ignores temporal and spatial limitations. It is one-track minded: to foster an increase in the population as a hedge against contingencies, which are outside the myth.

All the laws, which encourage optimization of resources, accommodation, an increase of order and negentropic results - belong, by definition to this meta-system. We can rigorously claim that there exist no laws, no human activities outside it. It is inconceivable that it should contain its own negation (Godel-like), therefore it must be internally and externally consistent. It is as inconceivable that it will be less than perfect - so it must be all-inclusive. Its comprehensiveness is not the formal logical one: it is not the system of all the conceivable sub-systems, theorems and propositions (because it is not self-contradictory or self-defeating). It is simply the list of possibilities and actualities open to humans, taking their limitations into consideration. This, precisely, is the power of money. It is - and always has been - a symbol whose abstract dimension far outweighed its tangible one.

This bestowed upon money a preferred status: that of a measuring rod. The outcomes of games and myths alike needed to be monitored and measured. Competition was only a mechanism to secure the on-going participation of individuals in the game. Measurement was an altogether more important element: the very efficiency of the survival strategy was in question. How could humanity measure the relative performance (and contribution) of its members - and their overall efficiency (and prospects)? Money came handy. It is uniform, objective, reacts flexibly and immediately to changing circumstances, abstract, easily transformable into tangibles - in short, a perfect barometer of the chances of survival at any given gauging moment. It is through its role as a universal comparative scale - that it came to acquire the might that it possesses.

Money, in other words, had the ultimate information content: the information concerning survival, the information needed for survival. Money measures performance (which allows for survival enhancing feedback). Money confers identity - an effective way to differentiate oneself in a world glutted with information, alienating and assimilating. Money cemented a social system of monovalent rating (a pecking order) - which, in turn, optimized decision making processes through the minimization of the amounts of information needed to affect them. The price of a share traded in the stock exchange, for instance, is assumed (by certain theoreticians) to incorporate (and reflect) all the information available regarding this share. Analogously, we can say that the amount of money that a person has contains sufficient information regarding his or her ability to survive and his or her contribution to the survivability of others. There must be other - possibly more important measures of that - but they are, most probably, lacking: not as uniform as money, not as universal, not as potent, etc.

Money is said to buy us love (or to stand for it, psychologically) - and love is the prerequisite to survival. Very few of us would have survived without some kind of love or attention lavished on us. We are dependent creatures throughout our lives. Thus, in an unavoidable path, as humans move from game to myth and from myth to a derivative social organization - they move ever closer to money and to the information that it contains. Money contains information in different modalities. But it all boils down to the very ancient question of the survival of the fittest.

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Why Do We Love Sports?

The love of - nay, addiction to - competitive and solitary sports cuts across all social-economic strata and throughout all the demographics. Whether as a passive consumer (spectator), a fan, or as a participant and practitioner, everyone enjoys one form of sport or another. Wherefrom this universal propensity?

Sports cater to multiple psychological and physiological deep-set needs. In this they are unique: no other activity responds as do sports to so many dimensions of one's person, both emotional, and physical. But, on a deeper level, sports provide more than instant gratification of primal (or base, depending on one's point of view) instincts, such as the urge to compete and to dominate.

1. Vindication

Sports, both competitive and solitary, are morality plays. The athlete confronts other sportspersons, or nature, or his (her) own limitations. Winning or overcoming these hurdles is interpreted to be the triumph of good over evil, superior over inferior, the best over merely adequate, merit over patronage. It is a vindication of the principles of quotidian-religious morality: efforts are rewarded; determination yields achievement; quality is on top; justice is done.

2. Predictability

The world is riven by seemingly random acts of terror; replete with inane behavior; governed by uncontrollable impulses; and devoid of meaning. Sports are rule-based. Theirs is a predictable universe where umpires largely implement impersonal, yet just principles. Sports is about how the world should have been (and, regrettably, isn't). It is a safe delusion; a comfort zone; a promise and a demonstration that humans are capable of engendering a utopia.

3. Simulation

That is not to say that sports are sterile or irrelevant to our daily lives. On the very contrary. They are an encapsulation and a simulation of Life: they incorporate conflict and drama, teamwork and striving, personal struggle and communal strife, winning and losing. Sports foster learning in a safe environment. Better be defeated in a football match or on the tennis court than lose your life on the battlefield.

The contestants are not the only ones to benefit. From their detached, safe, and isolated perches, observers of sports games, however vicariously, enhance their trove of experiences; learn new skills; encounter manifold situations; augment their coping strategies; and personally grow and develop.

4. Reversibility

In sports, there is always a second chance, often denied us by Life and nature. No loss is permanent and crippling; no defeat is insurmountable and irreversible. Reversal is but a temporary condition, not the antechamber to annihilation. Safe in this certainty, sportsmen and spectators dare, experiment, venture out, and explore. A sense of adventure permeates all sports and, with few exceptions, it is rarely accompanied by impending doom or the exorbitant proverbial price-tag.

5. Belonging

Nothing like sports to encourage a sense of belonging, togetherness, and we-ness. Sports involve teamwork; a meeting of minds; negotiation and bartering; strategic games; bonding; and the narcissism of small differences (when we reserve our most virulent emotions - aggression, hatred, envy - towards those who resemble us the most: the fans of the opposing team, for instance).

Sports, like other addictions, also provide their proponents and participants with an "exo-skeleton": a sense of meaning; a schedule of events; a regime of training; rites, rituals, and ceremonies; uniforms and insignia. It imbues an otherwise chaotic and purposeless life with a sense of mission and with a direction.

6. Narcissistic Gratification (Narcissistic Supply)

It takes years to become a medical doctor and decades to win a prize or award in academe. It requires intelligence, perseverance, and an inordinate amount of effort. One's status as an author or scientist reflects a potent cocktail of natural endowments and hard labour.

It is far less onerous for a sports fan to acquire and claim expertise and thus inspire awe in his listeners and gain the respect of his peers. The fan may be an utter failure in other spheres of life, but he or she can still stake a claim to adulation and admiration by virtue of their fount of sports trivia and narrative skills.

Sports therefore provide a shortcut to accomplishment and its rewards. As most sports are uncomplicated affairs, the barrier to entry is low. Sports are great equalizers: one's status outside the arena, the field, or the court is irrelevant. One's standing is really determined by one's degree of obsession.

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next:   Form and Malignant Form The Metaphorically Correct Artist and other Romanticist Mutations