SAN Case-Control Study

Feinstein AR, Heinemann LAJ, Dalessio D, Fox JM, Goldstein J, Haag G, Ladewig D, O'Brien CP.

Do Caffeine-containing analgesics promote dependence? A review and evaluation.

Clin Pharmacol Ther 2000; 68: 457-467.

ABSTRACT

Objective: Debates about the suspected association between renal disease and use of analgesics have led to concern about whether caffeine could stimulate an undesirable overuse of phenacetin-free combined analgesics. A committee was asked to critically review the pertinent literature and to suggest guides for clinical practice and for consideration of International Regulatory Authorities.

Participants: A group of international scientists, jointly selected by the Regulatory Authorities of Germany, Switzerland and Austria and the Pharmaceutical Industry.

Evidence: All invited experts evaluated relevant literature, reports, and added further information and comments.

Conclusions: (1) Caffeine has a synergistic effectiveness with analgesics. (2) Although caffeine has a dependence potential, the potential is low. (3) Experimental data regarding dependence potential for caffeine alone may not correspond to the conditions in patients with pain. (4) Withdrawal is not likely to cause stimulation or sustainment of analgesic intake. (5) For drug-induced headache, no single nor combined analgesic was consistently identified as causative, and no evidence exists for a special role of caffeine. (6) Strong dependence behavior was observed only in patients using phenacetin-containing preparations, coformulated with antipyretics/analgesics and caffeine. This finding may have led to the impression that caffeine stimulates overuse of analgesics.

Summary: Although more experimental and long-term data would be desirable to show possible mechanisms of dependence, and to offer unequivocal proof of safety, the committee concluded that the available evidence does not support the claim that analgesics coformulated with caffeine, in the absence of phenacetin, stimulate or sustain overuse.

OBJECTIVES

During debates about the association between renal disease and non-phenacetin-containing combined analgesics, a special question has evoked considerable attention particularly in Europe: does caffeine coformulated with analgesics cause overuse or abuse of the combined analgesics? Although the risk of developing end-stage-renal disease might not be increased by non-phenacetin-containing combined analgesics, as compared with single-ingredient analgesics, regulatory authorities would view a stimulation of analgesic overuse by caffeine as undesirable per se.



Because these questions have recently evoked considerable media and political attention in Germany, Austria, and Switzerland, where various groups have sought protective regulatory action, the Federal Drug Authorities of those countries asked the pertinent members of the Pharmaceutical Industry to support a special ad hoc review of the available literature and evidence. The members of the review committees were chosen jointly by the Authorities and the Industry. The Industry gave an unconditional grant to the organizers to prepare and execute the meetings.

The first meeting of the Scientific Board of the Study Group on Analgesics and Nephropathy (SAN) was held in Potsdam, Germany, in June 1999, on non-phenacetin–containing combined analgesics and the risk of end-stage renal disease (ESRD) or of analgesic associated nephropathy (AAN). In a consensus statement, the committee concluded (1): ....that sufficient evidence is absent to associate non-phenacetin-containing analgesics with nephropathy, and (2) that a new epidemiologic study should be done to provide appropriate data for resolving the question1. In addition, a separate committee of specialists was asked to critically review the pertinent literature concerning a dependence potential of caffeine, particularly when combined with analgesics, to suggest guides for clinical practice and for consideration of Regulatory Authorities.

The main question to be answered was whether the literature contained sufficient evidence to conclude that caffeine coformulated with OTC analgesics (such as phenacetin, acetylsalicylic acid, paracetamol) causally stimulates or sustains analgesic use beyond therapeutic need. A subsidiary question was whether such usage, if it occurs, is due to a specific psychotropic interaction of caffeine with the analgesic agents.

Participants: A group of international scientists, jointly selected by the Regulatory Authorities of Germany, Switzerland and Austria and the Pharmaceutical Industry, held a one-day meeting on January 18, 2000 in New York, N.Y. The members of the committee are listed in the title of this report.

Evidence: The committee reviewed pertinent information from different sources: peer-reviewed papers, editorials, and any other appropriate publications, including those in books and supplements to journals. A first set of articles was sent to the members before the meeting, and further information was added during and after the meeting. Since the literature provides only rare data on the role of caffeine in analgesic use, special emphasis was placed on the question of interpreting analgesic activity in studies on the abuse potential of caffeine in coffee or other beverages.


CONSENSUS

GLOSSARY
For purposes of this document, the committee used the terms defined in the widely accepted World Health Organization's International Classification of Diseases (ICD-10)2. Terms in the section on "Mental and behavioural disorders due to use of other stimulants, including caffeine" are listed under F15.X in ICD-10, but not all fourth characters are applicable to caffeine2.The American Psychiatric Association's Diagnostic and Statistical Manual Fourth Edition (DMS-IV)3 uses definitions similar to the list that follows:

 

§ Overuse , Excessive Use, and Misuse were regarded as equivalent terms, referring to usage beyond therapeutic recommendations. The committee preferred the term overuse, which does not necessarily imply dependence.

§ Harmful use is defined in ICD-10 as: "A pattern of psychoactive substance use that is causing damage to health. The damage may be physical.....or mental....". The term "abuse" in DSM-IV has a similar definition.

§ Dependence syndrome is defined in ICD-10 as: "A cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state".

§ Withdrawal state is defined in ICD-10 as: "A group of symptoms of variable clustering and severity occurring on absolute or relative withdrawal of a psychoactive substance after persistent use of that substance. The onset and course of the withdrawal state are time-limited and are related to the type of psychoactive substance and dose being used immediately before cessation or reduction of use."

§ Tolerance means repeated use that leads to smaller effects from a given dose.

§ Physical dependence refers to the overuse withdrawal phenomenon and tolerance, whereas psychological dependence refers to loss of control over drug use.

§ Preferential use refers statistically to an overrepresentation of a pertinent drug or drug combination in pertinent usage. The preference may come from therapeutic efficacy; and the term does not necessarily represent dependence, or have any causal implication.

§ The term addiction was not used because it appears in neither ICD-10 nor DSM-IV and its definition varies widely. (For most purposes, the idea of "addiction" is conveyed by the term "dependence").

Synergistic Effectiveness of Analgesics coformulated with caffeine

Experimental data and pharmacological rationale 4-7, as well as clinical data8-9, demonstrate analgesic efficacy for caffeine alone. Experimental data10,11 and clinical evidence also show the synergistic analgesic efficacy of caffeine in coformulation with morphine or in coformulation with antipyretic analgesics or ibuprofen, respectively12-17. Based on the results of The Evaluation Committee B 3 (Neurology/Psychiatry) of the Federal Ministry of Health, the German Federal Institute of Health (Bundesgesundheitsamt – BGA) concluded that caffeine shows synergistic efficacy when co-formulated either with acetylsalicylic acid18 or paracetamol19.

Recent clinical studies20,21 have confirmed previously obtained results22 and conclusively demonstrated a relevant analgesic synergism when antipyretic analgesics are coformulated with caffeine. The combination of acetylsalicylic acid, paracetamol and caffeine is the first over-the-counter preparation for which efficacy in the treatment of common migraine headaches has been demonstrated in a parallel-group study with an appropriate design23,24. These results led the compound analgesic receiving FDA-approval as the first preparation for migraine self-medication24. The committee concluded that this analgesic synergism could plausibly explain a preferential use of combined caffeine-containing analgesics over single analgesics.


Dependence potential of Caffeine in Coffee and other beverages: Experimental studies

The question of dependence on caffeine in coffee drinkers was amply studied in groups led by Goldstein et al.25,26, Griffiths27-33 and Hughes34-36 and more recently by Dews37. These results have been reviewed by Nehlig38 .


Caffeine Dependence( F15.2 of the ICD-10)

The committee reviewed the existing data for the separate aspects of physical dependence (withdrawal, tolerance) and of psychological dependence (reinforcing properties, caffeine discrimination, and CNS rewarding system).


Physical dependence

After sudden and complete cessation (deprivation) of caffeine, typical manifestations of withdrawal begin to occur after 12 - 24 hours, peaking after 20 to 48 hours39-42 and sometimes lasting a week. The most often reported manifestations are headaches, feeling of weariness or lethargy, weakness and drowsiness, impaired concentration, fatigue, and difficulty in work. Less frequent manifestations are depression, anxiety, irritability, increased muscle tension, occasional tremor, and nausea and vomiting29,32,33,42-45. Some manifestations simply reflect the absence of expected caffeine stimulant effects, whereas others are truly time-limited pharmacological withdrawal reactions.

Withdrawal symptoms are poorly related to the quantity of caffeine ingested daily29,32,35,46-48, and can occur even with cessation of small doses such as 100-200 mg. Conversely, the symptoms may not occur after cessation of large doses such as 500 mg. The caffeine withdrawal symptoms disappear immediately after resumption of caffeine intake25,26,36,46,49. Most of the cited studies were done using caffeinated beverages in which caffeine stimulant effects are expected. Most analgesics users, however, probably do not expect stimulant effects from analgesics. Thus, it is not clear how much of the caffeine withdrawal phenomena would occur when caffeine-containing analgesics are stopped.
In dose-ranging experimental choice tests, with subjects categorized as caffeine choosers or non-choosers, caffeine-deprived choosers tended to report both positive subjective effects of caffeine on mood and vigilance, as well as negative subjective effects such as headache and fatigue. Caffeine non-choosers, on the other hand, tended to report negative effects of caffeine such as anxiety and dysphoria31,50,51. Studies by the Griffiths group indicate29,31 that in trained subjects caffeine can be discriminated at quite low levels, but the group do not feel that this is relevant to untrained subjects.

Tolerance occurs, especially in animals, for some of the physiological (including aversive) effects linked to the regular consumption of coffee50,52-56. In humans, the data are less conclusive, and the difference may be due to individual levels of susceptibility and tolerance to caffeine-induced effects. Moreover, mechanisms of tolerance may be overwhelmed by the non-linear accumulation of caffeine and its main metabolites when caffeine reaches steady-state levels in the human body under multiple dosing conditions53,57.


After the description in 1943 by Driesbach & Pfeiffer49, headache due to withdrawal of caffeine was originally suspected by nephrologists58 as causing further analgesic consumption. This suspicion, although later regarded as a scientifically based hypothesis59-62, did not take into account the lag-time of 12-24 hours until withdrawal symptoms occur after complete deprivation of caffeine. Since caffeine is ubiquitously and easily available in beverages, a withdrawal syndrome due to discontinuation of caffeine-containing analgesics is not likely to develop under daily conditions.

Psychological dependence

In animals, robust self-administration, i.e., drug-reinforcement, is a major criterion of the potential for psychological dependence. In animal experiments, classical drugs of abuse are consistently maintained across species and conditions63,64, but caffeine, when restricted only to certain human conditions, elicits a sporadic pattern of intake63,65-69 compared with self-administration of classical drugs of abuse.

In humans, mildly reinforcing properties of caffeine self-administration are found primarily in the form of caffeinated beverages27,70. The choice of caffeine can be influenced either by the desire to avoid withdrawal symptoms or by its positive effects.43,72. Moreover, the taste of coffee or other caffeinated beverages is an important aspect of caffeine consumption73,74, demonstrated in experimental settings by subjects who prefer caffeine in beverages to caffeine in capsules48,75.

A recent double-blind caffeine manipulation study37, however, showed that most subjects with a past history of caffeine withdrawal did not actually develop withdrawal symptoms. In many other studies, the human subjects have not been fully blinded, i.e., they actually knew they were participating in a "caffeine study". The result of blinded studies may be most relevant in the context of analgesics, because consumers unaware of the caffeine content can get additional caffeine from beverages.

In a review of data from double-blind placebo-controlled studies on ibuprofen and caffeine administered, either alone or in combination, the group receiving caffeine-containing capsules were not found to have discernible overusage76. This study, on combinations of analgesics in patients with pain, is particularly relevant for the current review.



Other indices of dependence

Drugs producing psychological dependence have psychoactive effects that can be determined either by experimental discrimination studies, or by studies on mood and behaviour. In experimental studies using capsules to avoid the role of taste, caffeine was easily discriminated from placebo at doses of > 300 mg, mainly by the negative effects of jitters, anxiety, or nervousness. Doses in the range of 50-150 mg - as commonly used in OTC analgesics - were poorly detected.51,77,78 Whether this discriminative capacity occurs in long-term users of caffeine-containing analgesics is unknown. In other studies, doses of caffeine less than 100 mg were believed to affect mood or enhance vigilance79-81 in some persons.

Drugs that produce psychological dependence also increase dopamine in the brain reward system64. The interaction of caffeine with dopaminergic transmission has a "mechanism ... very different from that of other drugs such as cocaine and amphetamine" (see Fredholm83 for review; also Nehlig38).In doses equivalent to human consumption (200-300 mg) caffeine does not act like typical drugs of abuse38 to increase dopamine release in the shell of the nucleus accumbens. In fact, "the effect in nucleus accumbens is manifest as a decrease in activity of the cells involved, whereas the effects of cocaine and amphetamine are associated with an increased activity of the relevant cellular targets"83. Higher doses of caffeine can induce increased rates of cerebral glucose utilisation in the shell and the core of nucleus accumbens82,84. The effect "differs from specific metabolic changes in the shell of the nucleus accumbens recorded with drugs of abuse"38. Moreover, that doses of caffeine can lead to widespread cerebral metabolic increases, i.e., apparently an unspecific effect; conversely drugs like amphetamine, cocaine, and nicotine elicit increase of functional activity in distinct other brain areas only64,85-87. Lower doses of caffeine activate the motor system and sleep-wake cycle, resulting in increased vigilance82,84.

Another factor in determining psychological dependence is the rapidity of drug effects. The oral consumption of caffeine usually occurs gradually over the day88, not in a large single dose.

CONCLUSION

The committee had three main conclusions on this topic: (1) Although caffeine has a dependence potential, the potential is low. (2) The experimental data may not correspond to the real world conditions of analgesic overuse in pain patients. (3) It appears unlikely that withdrawal could play a causative role in stimulating or sustaining analgesic intake, because of the wide availability and the low dependence potential of caffeine, the pharmaceutical availability of pure caffeine in pills or capsules, and the lack of evidence for abuse of caffeine in pharmaceutical form.


Drug-induced headache

The term "drug-induced headache" has been used to refer to two distinct phenomena: (1) headache regularly occurring 2-3 hours after ingestion of analgesics, still during the period of efficacy of the analgesic, and (2) severe headache after complete withdrawal of analgesics, lasting for a few days and making drug withdrawal extremely difficult without clinical assistance.

(1) Headache induced by chronic substance use or exposure

In headache patients, overuse and long-term use of analgesics and migraine remedies may cause drug-induced headache that should be distinguished from withdrawal headache (as discussed later). The Headache Classification Committee of the International Headache Society (IHS) in 198889, offered the following diagnostic criteria under "8.2. Headache induced by chronic substance use or exposure":

 

- Occurs after daily doses of a substance for >3 months.

- A certain required minimum dose should be indicated.

- Headache is chronic (15 days or more a month).

- Headache disappears within 1 hour after further intake of analgesics.

An additional comment88 stated: ”So far headache induced by chronic use of ergotamine and analgesics has only been described when the drugs have been taken for a headache disorder, not when they have been taken for other disorders.”

The IHS criteria define two subgroups: ergotamine-induced headache (8.2.1) and analgesic abuse headache, but it is now also known that migraine-specific triptans can cause drug-induced headache. According to the IHS, the pre-condition for inducing analgesic-abuse headache is the ingestion of 100 tablets a month of analgesics combined with barbiturates or other non-narcotic compounds, or 50 g of acetylsalicylic acid a month or equivalent of other mild analgesics. The IHS does not assign any particular role to caffeine-containing preparations in the development of drug-induced headache.

In Central Europe, particularly in Germany and Austria, combined preparations - such as two analgesics, analgesic plus migraine remedy, analgesic plus caffeine, and analgesic plus codeine - are suspected of leading to drug-induced headache more often than single substances90. This suspicion comes from studies showing that a high percentage of the examined patients with drug-induced headache had used combined preparations91-93. This finding, however, reflects the then existing market situation (headache patients frequently used combined preparations) and may not reflect preferential use, and thus does not permit causal conclusions.

For example, Rapoport94, in a survey of 1974 practices in the USA, found the use of a great variety of different analgesic agents: paracetamol (27%), butalbital + aspirin + caffeine (24%), aspirin (19%), other butalbital combinations (19%), paracetamol/codeine combinations (15%), opioids (13%), nasal decongestants (10%), other NSAIDs (5%), barbiturates (10%), and ergotamine (9%). Caffeine in form of coffee and other beverages was concomitantly overused in nearly 50% of patients as were tobacco (43%) and alcohol (14%).94 Thus, caffeine as a component of analgesics was not identified as a specific cause of drug-induced headache.

A similar distribution of agents in Germany was found by Scholz et al90, who determined that patients with drug-induced headache consumed a dose tenfold higher than that used by the typical migraine patient. The authors said, "Since caffeine is included in most of the anti-migraine drugs and analgesics in Germany it was inevitably taken...The overall intake of 300 mg of caffeine in our chronic headache group seems to be only a moderate dosage since 20-30% of a normal population report consumption of more than 500-600 mg per day"90.


In conclusion, no single analgesic was consistently identified as strongly associated with drug-induced headache, and no evidence was found that caffeine plays a distinctive role.

(2) Headache due to withdrawal of analgesics (formerly called: rebound headache)

The IHS diagnostic criteria89 for headache from substance withdrawal (chronic use) include:

 

- Occurs after use of a high daily dose (specified for each substance when possible) of a substance for > 3 months.

- Occurs within hours after elimination of the substance.

- Is relieved by renewed intake of the substance.

- Disappears within 14 days after withdrawal of the substance.

A withdrawal headache can occur after intake of single analgesics, combined analgesics, or specific migraine remedies (ergotamines, triptanes). With caffeine-containing combined analgesics, an additional caffeine withdrawal headache may occur if patients ingested caffeine daily at levels of at least 15 g per month. There is no evidence, however, that the headache on withdrawal from caffeine-containing analgesics is more severe or problematic than on withdrawal from other substances.

In addition, the caffeine withdrawal headache (IHS 8.4.2.) is milder and easier to overcome than the drug-induced withdrawal headache after withdrawal of analgesics. The general belief in the scientific community, therefore, is that drug-induced headache is mainly due to the intake of doses of analgesic drugs about 10-fold higher than those used by migraine patients93. The mechanism is unclear, but drug-induced headache occurs only in patients with pre-existing headache, who may have an underlying special mechanism for vulnerability92.

Is phenacetin a primary cause of Dependence to analgesics?

The dependence potential of phenacetin in analgesics is important because nephrologists have promoted the hypothesis of a possible dependence to antipyretic analgesics, for which phenacetin combined with caffeine was originally suggested as possibly responsible58,59,95. Because overuse of phenacetin-containing analgesics is regarded as the major cause of analgesic-associated nephropathy, the nephrologists' concern helped evoke the current review.

Before the ban of phenacetin (and of barbiturates or bromides in analgesics), caffeine had not been accused of causing overuse of analgesics. After the ban, the problem of analgesic overuse subsided, e.g., in Switzerland (Ladewig personal communication) and also in Sweden96,97, even though the highest portion of caffeine-containing analgesics is sold today in Sweden98. As noted earlier, the US FDA recently approved a caffeine-containing analgesic combination for over-the counter use in self-medication of migraine24. Neither official spontaneous reporting systems of drug adverse reactions in different countries18,19, or systematic clinical trials37 after the phenacetin era produced evidence of a dependence potential of caffeine-containing analgesics.

On the other hand, during the phenacetin era, nephrologists observed typical dependence behaviour in patients with nephropathy who preferably used preparations providing a high bioavailability of phenacetin, such as the powders ASKITâ in Scotland58, BEXâ and VINCENTâ in Australia99, HJORTENSâ in Sweden96, and WITTE-KRUISâ, MANNâ and PERDOLANâ in Belgium61,100.


A typical patient's behaviour was described by Murray58 (and by others96,101) as follows: The nephropathy self - medicators were more likely to take ASKITâ powders than other preparations. Duration of ingestion was from 4 to 45 years; and the average total intake was 14 kg phenacetin (3 to 69 kg). Of 51 patients, 24 took the analgesics because of their mood altering effects ("they give me a lift"; "an ASKITâ is heaven, doctor"), and 39 believed that their analgesic ingestion "had become a habit". Relatives' estimates of intake were often 3 or 4 times higher than patients confessed; and 31 of the 51 patients continued their analgesic habit against family opposition. In some cases the family had hidden or destroyed the analgesics, and in a few, the patients were denied money to buy the drugs. Among family opinions were: "she seems to need them"; "she's an addict"; "she's doped silly with ASKITâ". Murray58 wrote, "For at least 20 of 51 patients, knowledge of the consequences of analgesic abuse was not deterrent to continued consumption" ..... "Most of the patients had absolute faith in the efficacy of their favourite preparation, and would go to great length to obtain it". A chemist stated: "When supplies of a patient's favourite powder ran out, she would get like a wreck". A husband stated: "She is like a mad thing without a BEECHAMS".

These accounts fulfil the criteria of the dependence syndrome listed earlier in the ICD-10 glossary: a strong desire to take the drug, difficulties in controlling its use, and a higher priority given to drug use than to other activities and obligations. This dependence behavior was not observed with non-phenacetin analgesic preparations containing caffeine, nor with caffeinated beverages27,35,102,102. It is clear that caffeine, though it shows brain stimulating effects, does not cause the type of compulsory drug use behaviour found with phenacetin under certain circumstances (high intake plus high absorption). It seems likely that phenacetin's strong dependence potential was possibly synergistically enhanced in combination with caffeine. This hypothesis was originally proposed by nephrologists58,59 in the only two citations of possible causes of analgesic overuse mentioned in nine epidemiologic studies of analgesic nephropathy103.

The committee noted the following evidence: Phenacetin has alone been reported to have psychoactive effects95,104. In an experimental human study, Kincaid-Smith99 reported that "it was after the removal of phenacetin and not caffeine that patients noticed the loss of the mood-altering properties of compound analgesics". Furthermore, physicians studying analgesic-associated nephropathy have remarked that they believed their patients were habituated or addicted105-114 although the WHO Expert Committee115 did not consider the possibility of dependence on antipyretic analgesics.

In a crucial experiment, Prescott95 gave volunteers fine, medium, and coarse suspensions of phenacetin (particle size < 75 mm; 150-180 mm; > 250 mm), and tablets of 2 proprietary brands (analgesic combinations). Plasma concentrations were determined for phenacetin and its major metabolite, paracetamol; and central nervous system effects were measured. Phenacetin is effectively degraded to paracetamol and minor metabolites, so that considerable plasma concentrations of phenacetin are only achieved with the quick absorption found solely with the fine suspension. It produced "alarming" but "not unpleasant" effects, which were somewhat similar to intoxication with alcohol. These effects did not occur with other preparations that produced high paracetamol concentrations . Eade & Lasagna104 found that phenacetin tended to produce unpleasant effects – headache, dizziness, clumsiness (similar to barbiturate reactions) – but paracetamol could not be distinguished from placebo for central nervous system effects. These results supported the findings of Prescott95 that phenacetin has actions on the central nervous system not shared by paracetamol. In addition, Murray & Smith116 reported patients showing co-existing analgesic-associated nephropathy and bromism, who were clearly addicted to powders containing two drugs, phenacetin and bromide, that had been produced by a pharmacist for customers as a headache powder. Bromide was one component in PERDOLANâ100, a frequently used analgesic powder in Belgium. Beside the dependence potential of phenacetin-containing analgesic powders, additional factors contributing to analgesic overuse have been predisposing personality factors, and also occupationally stimulating situations as in the Swiss watch industry117,118, in Swedish factories96, or in advertising work119,120.


Personality factors have been investigated systematically by Ladewig102,121,122 and RM Murray58: Ladewig did a 6-year follow up121,122 in a subgroup of consumers (high intake, low intake) and controls of the prospective cohort study of Dubach117,118. RM Murray examined personality traits and motivations in several controlled studies of phenacetin-abusers119. Taking into account a different scope and different national settings (Scotland, Switzerland), the results of both investigations were almost identical and are supported by numerous observational data from Canada101, Belgium60,61, and Australia120,123.

The basic findings were that there is no typical psychological profile or personality structure leading to drug-dependence. Nevertheless, patients with analgesic-associated nephropathy, as compared with controls, differed in higher general psychosomatic disturbances, higher irritability tinged with dysphoria, psychological and emotional immaturity, and lability and disturbances in sexual identity102,121,122. Patients who showed both a family history of psychiatric disorders and abuse of analgesics were more likely to have had previous psychiatric treatment for such diagnoses as neurotic and depressive reactions, personality disorders, and anxiety states. Additional factors were alcoholism or drug dependence, and smoking more than 20 cigarettes a day. Two-thirds of the patients suffered from chronic insommia, and 14% had attempted suicide58. Typically these patients were introverted neurotics "who would be reluctant to seek analgesics from their doctors, and might instead resort to self-medication of their pain. Introverts develop conditioned reflexes more easily than extraverts, and would, therefore, more readily associate the pleasurable mood altering effects of compound analgesics with the act of analgesic-taking"58.

Our committee concluded that typical strong dependence behaviour to analgesics was observed only in patients using phenacetin-containing preparations, coformulated with antipyretics and caffeine, particularly in powders that provided quick absorption. A synergistic effect of phenacetin and caffeine cannot be excluded, and may even be likely, but has not been adequately investigated. There is no evidence that other antipyretic analgesics - such as acetylsalicylic acid, pyrazolones, ibuprofen, and in particular paracetamol96 - share the actions of phenacetin on the central nervous system. Consequently, it seems plausible and likely that phenacetin (in powders) was the major cause of overuse of analgesics in susceptible individuals with analgesic-associated nephropathy.

CONCLUSIONS

The absence of suitable evidence of "danger" does not necessarily offer unequivocal proof of "safety". To provide such a proof, however, would require much more experimental and long-term data on possible mechanisms of caffeine dependence. Since the additional data may not be obtained for many years, if at all, the committee agreed that sufficient evidence does not exist for the claim that analgesics coformulated with caffeine, in the absence of phenacetin, stimulate or sustain overuse.

Suspicions that caffeine combinations of analgesics might lead to dependence behavior are not supported by data, except in formerly used combinations with phenacetin. The dependence behavior noted with phenacetin-caffeine combinations probably arose because accentuated absorption of phenacetin in powders produced particularly high bioavailability.

There is no evidence that caffeine-containing analgesics are more responsible for the development of drug induced headache than other analgesics alone or migraine drugs alone. There is also no evidence that the withdrawal of caffeine-containing analgesics is more difficult than for other analgesics or other headache inducing drugs. Because of the difficulty of proving "safety", contentions of "danger" for caffeine must be sustained by adequate evidence. If dangers exist, however, they have not been convincingly demonstrated in the available data.


ACKNOWLEDGMENTS

The review group thanks the Drug Regulatory Agencies of Germany (Bundesinstitut für Arzneimittel und Medizinprodukte), Austria (Bundesministerium für Arbeit, Gesundheit und Soziales), and Switzerland (Interkantonale Kontrollstelle für Heilmittel) for their initiative, and for raising appropriate questions to be reviewed. We thank the Steering Committee for "Caffeine-containing Combined Analgesics" of German Medicines Manufacturers for facilitating the group’s one-day meeting with a unconditional grant.

We also thank John R. Hughes, M.D., Dept. of Psychiatry, University of Vermont School of Medicine, for consulting with us and his helpful critical comments.

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