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Abstract—Two psychonautic bioassays (self-experiments) in stepwise and abrupt cessation of longterm daily oral ingestion habits of 800 mg of codeine phosphate are presented. Concomitant administration of minute doses (about 0.5 meg) of the opioid antagonist naltrexone with each dose of codeine was found in both cases to obviate the expected opioid withdrawal syndrome, resulting in asymptomatic and uneventful transitions from physical opioid dependency states to exogenous opioidfree metabolism. These experiments are analyzed in the context of a conjectured, rapid, iterative reduction and complete elimination of opioid tolerance, once acquired. It was found that coadministration of naltrexone with codeine phosphate obviated the development of both tolerance and physical dependency over several months of four daily oral doses of 200 mg, allowing abrupt ("cold turkey"), asymptomatic and uneventful withdrawal. This points the way to the biochemical substrate of opioid tolerance itself, and shows that this can easily and inexpensively be blocked, even over months of iterative oral administration of substantial doses of opioid analgesics. Finally, it suggests the opioid withdrawal syndrome is directly related to the physiology of opioid tolerance, and can be prevented by blocking tolerance itself. Even when tolerance has been acquired, this can be reduced stepwise over a matter of days, with no symptoms of opioid withdrawal syndrome. Keywords—addiction, codeine, naltrexone, opioids, tolerance, withdrawal
Like progressive toleratice to their atialgesic atid euphoric effects, the well-ktiowti opioid withdrawal sytidrome is thought to be ati ineluctable sequel to cessatioti of habitual use of opioids, at high etiough dosage and for sufficient duration. However, several classes of compotinds are known in animal ttiodels to ameliorate and even to
tThe author is indebted to Richard Heffem for valuable advice and consultation. •Partner, Entheobotanica, Solothum, Switzerland. Please address correspondence and reprint requests to Jonathan Ott, Entheobotanica, Kronengasse, 11, Solothum CH-4502, Switzerland.
prevent the development of opioid tolerance, and also to attenuate the allied withdrawal syndrome, a phenomenon I recently dubbed "anti-Mithridatism"' (Ott 1997). Examples of anti-Mithridatism are the use of dizocilpine, also known as MK-801 (Trujillo & Akil 1991), and proglumide (Watkins, Kinscheck & Mayer 1984). Based likewise on animal models, it has lately been reported that nano- and picomolar doses of naltrexone, coadministered with opioids, could not merely enhance their analgesic potency, but attenuate the withdrawal syndrome occasioned by their
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withdrawal from dependent animals. This follows the intriguing discovery that the m-opioid receptors that mediate analgesia exist as two types on nociceptive neurons (painsensitive neurons): apart from the prototypical inhibitory |i-receptors, there is a much smaller population of excitatory ^.-receptors, opioid binding to which produces hyperalgesia (Crain & Shen 1996). In this innovative technique, which is currently undergoing clinical trials by Pain Therapeutics, Inc. (using MorViva® and OxyTrex®),^ minute doses of the potent opioid antagonist naltrexone (ca. 1: 100,000 in relation to opioid doses, expressed as molar equivalents of base) apparently block preferentially these hyperalgesic, excitatory m-receptors, and in effect "unmask" the true analgesic potency of opioids. Being a long-time (ca. 25 years) daily user of medicinal opiates (chiefly morphine sulfate peroral, up to 300 mg/ day, and codeine phosphate peroral, up to 1.6 g/day), I am well familiar with the opioid withdrawal syndrome, best detailed in human studies by the U.S. Public Health Service at the erstwbile federal "narcotics farm" prison in Lexington, Kentucky (Kolb & Himmelsbach 1938; Small et al. 1938). When I learned of this biphasic, mixed analgesic/hyperalgesic activity of opioids in animals, I at once resolved to ascertain whether it were operative in human beings. Using pharmaceutical codeine phosphate of known dosage and unmixed with aspirin or other drugs, and standard solutions of pharmaceutical naltrexone hydrochloride (Antaxone®, which allowed precise oral or sublingual application of 0.5 meg doses, expressed as naltrexone base), I began their concomitant administration. At roughly a 1: 100,000 (as molar equivalents) ratio of naltrexone base to codeine base, peroral, there was approximately a 30% increase in potency, as assessed by subjective (euphoric) effects, in contrast to crude tests for analgesia in common use by pharmacologists, despite the fact that I was then taking 800 mg/day codeine phosphate peroral, divided into four doses of 200 mg each. I assert that an experienced opioid habitue, who knows dosage amounts precisely, is able to make rather good subjective assessments of potency—a methadone-maintainee, for instance, would know soon enough if a reduced or enhanced dose had mistakenly been administered. So dramatic and incontrovertible was this potentiation, that I at once reasoned it should follow that a 25% reduction in codeine dosage cum naltrexone would be perceived as being equipotent with my habitual dose of codeine neat. This proved to be a palpable hit: it was indeed equipotent. This suggested that the biochemical substrate of opioid tolerance (which remains as inscrutable as ever, despite exhaustive research) is amenable to pharmacological readjustment in real time, as it were. It followed inexorably, then, that in principle an opioid habitud could stepwise rachet-down tolerance; indeed, reduce the dose to zero, absent the opioid withdrawal syndrome. This also proved to be true, as will be evident from my two selfexperiments.
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ETHICS OF SELF-EXPERIMENTION WITH PSYCHOACTIVE DRUGS In peer-review of this article, the issue of ethics was raised: specifically regarding the fact that this research "was not conducted under the auspices of an Institutional Review Board" (IRB), nor a physician's supervision. In a prior article in this journal, I have already addressed the ethical dimensions of purportedly "objective" pharmacological research with animals, as opposed to "subjective" human self-experimentation (Ott 2001). As far as the IRB is concerned, such does not apply here, insofar as the research was not conducted at any institution, nor involved any subject other than the experimenter. EXPERIMENT 1: MAY-JUNE 2001 I am the subject, then aged 52 and in good health. I was taking daily 800 mg codeine phosphate peroral as four 200 mg doses (Perduretas®), and had maintained tbis habit for over a year, at times taking 1.0-1.6 g codeine phosphate daily. I resolved to reduce my habitual dose stepwise over 14 days, with tbree plateaus (where a given dose is repeated a second day). I followed a valuable practice: each daily dose was taken a balf-bour later in tbe day, that is, 24.5 hours elapsed between doses (25 hours is probably better). As bas been known since De Quincey's day, it is unproblematic to reduce one's dose by one-balf, and so tbe day before commencing, I simply prescinded (or eliminated) two of my customary four doses, thus taking 400 mg. Table 1 shows tbe reduction schedule. Each codeine dose was accompanied by 0.5 meg naltrexone base, excepting Day 1, wben the dose was 1.0 meg. I experienced only tbe slightest withdrawal symptoms on Day 1 (neck and shoulder tension starting 1.5 hours before dose time) and on Day 2 (similar tension two bours before dose time, and slight goose flesh 0.5 hours prior). This was likely due to an overly abrupt initial reduction in dosage. Apart from tbis, I passed a completely asymptomatic and uneventful witbdrawal, in the course of wbich I ate, slept and worked normally. Althougb tbere was some "clock-watcbing" up to Day 3, on Day 9 I forgot tbe time and took my dose an hour late. Following merely 36 hours of total abstinence (having been asymptomatic for 13 days and after 10 days at doses beneatb 10% of the habitual), on tbe morning of Day 15 and again that evening, I took two 120 mg doses of codeine phosphate, wbich of course gave good euphoric effects. Then on Day 16, 24 bours after tbe second dose of codeine, I conducted a naltrexone-challenge test, by taking 25 mg naltrexone peroral, wbicb would bave precipitated withdrawal symptoms bad I somehow been mistaken in my appraisals, or had the prompt resumption of codeine intake for one day reestablished physical dependence. Althougb I could indeed perceive the "anti-opioid" nature of naltrexone, absolutely
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Obviation of Opioid Withdrawal Syndrome
Codeine-Withdrawal Reduction-Schedule (Experiment 1)
Day 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
400 mg 160 mg 144 mg 120mg 120mg 96 mg 80 mg 80 mg 64 mg 48 mg 48 mg 40 mg 32 mg 24 mg Omg 240 mg
Total Reduction 50% 60% 64% 70% — 76% 80% — 84% 88% — 90% 92% 94% 100% —
% Reduction 50% 60% 10% 17% — 20% 17% — 20% 25% — 17% 20% 25% — —
Week 1: 800 mg
Week 2: 256 mg
Naltrexone (25 mg) Challenge
no withdrawal symptoms supervened. Out of curiosity, over the next 72 hours, I made six "codeine-challenges" of naltrexone. Doses of 160 mg codeine phosphate at two, three, 24, 38, 64 and 72 hours post-naltrexone were taken. Not until 64 hours was any opioid effect perceived, perhaps 50% attenuated. At 72 hours, naltrexone blockade of m-receptors had ceased, which agreed with my calculations based on data showing an approximate four-hour tissue halflife for naltrexone. EXPERIMENT 2: JUNE 2002 I again maintained a habit of 800 mg/day codeine phosphate peroral for several months, always administering each 200 mg dose of codeine with 1.0 meg naltrexone orally or sublingually. Given the above self-experiment, it seemed lo me possible that not only might I develop no tolerance to codeine-effects, but that such a habit could abruptly be terminated without occasioning any withdrawal syndrome. In this case, I merely dropped my daily dose to 200 mg over three days by the simple expedient of daily prescinding one of my habitual doses. On the fourth day and thenceforth until this writing two months later, I abstained completely from codeine or other opioid analgesic. Although I felt weary on my first opiate-free day, I slept normally and experienced not the slightest trace of any opioid withdrawal syndrome.
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I might add parenthetically that throughout the course of four daily doses of 200 mg codeine phosphate, solid euphoric effects followed each by some 30 minutes (the pills were crushed in a mortar and partially dissolved in hot water), suggesting tolerance was not developing. On the other hand, absent naltrexone, this is normal in my experience—despite development of progressive tolerance, a controlled user who knows dose precisely can stabilize at a mid-level dose, experience pleasant, but not overwhelming, opioid euphoria, and maintain that situation indefinitely. It is worth noting that exaggerated attention is focused on uncontrolled users with no idea of dosage, nor indeed purity, much less identity, of their opioids. Meanwhile, the United States, with roughly 4% ofthe world's population, in 1994 consumed 700 tons or 50% of the world's licit opium production, which is to say 13 times world per capita consumption (International Narcotics Control Board, cf. Marnell 1995). Most of this raw material for opiate pharmaceuticals is converted to codeine, much simply extracted and purified as morphine salts, some transformed to potent, artificial opiate derivatives like oxycodone and oxymorphone. Now, 700 tons of opium (even at a conservative 10% morphine), represents 70 tons of morphine (or 70,000,000 g). Assuming a daily oral habit of 100 mg (which I can attest certainly leads to physical dependency; vide also Burroughs 1959, 1953), 36.5 g per year would maintain one "addict," and 70 tons in principle could
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support nearly two million such habits. This is certainly a higher number than the total population of heroin users, and surely there exist at least as many medicinal opioid "addicts" as "junkies," whether by medical necessity or personal choice. COMMENTARY The two experiments of opioid withdrawal described here—completely novel in my long experience with such— may well represent the first reports ever of truly asymptomatic withdrawal of opioids following long-established habituation to significant and multiple daily doses. While of course no comparison can be made to intravenous injection of street heroin in terms of analgesic potency in human beings, 800 mg of codeine phosphate peroral is equivalent to 240 mg of morphine sulfate or 120 mg of oxycodone hydrochloride peroral (Beers & Berkow 1999). What is being discussed here is the obviation, not of opioid habituation per se, but of aspects of tolerance and physical dependence, heretofore thought to follow like night, the day of cessation of an opioid habit of such dosage-level and duration as to constitute so-called "addiction." The term "addiction" is used so loosely and tendentiously, and has been subject to so many redefinitions and qualifications, as to render it too imprecise for scientific use. The physical withdrawal syndrome was once held to be the sine qua non of addiction (Small et al. 1938) until a paradigm-shift occurred in the 1980s. Whereas prior to this, negative reinforcement (i.e., avoidance of the pain of withdrawal) had been held to be the primary motor of addiction, positive reinforcement (rewarding effects) came to displace it, and today the drugs considered to have the highest "addictive liability" are the stimulants, notably cocaine, amphetamines and nicotine, the withdrawal of which from habitues occasions no physical withdrawal syndrome of note. Despite politically-inspired efforts to conjure a cocainic withdrawal syndrome, in my long experience and based on observations and interviews of more than 100 habitues, nothing resembling the opioid withdrawal syndrome accrues on cessation of habitual use, irrespective of its duration and dosage-levels. The same is true for nicotine, even after prolonged sublingual use exceeding 100 mg/ day of nicotine free-base (this will be the subject of another report). "Mcofine-habituation" is often used carelessly to describe "tobacco-smoking habituation." The so-called "tobacco-smoking withdrawal-syndrome" does not appear to be based on physical dependency on nicotine (present at low, nonpsychoactive levels in commercial tobacco; ca. 1.0 mg/cigarette). To obviate the physical withdrawal syndrome of opioids, while it perforce removes negative reinforcement aspects of the habit, nonetheless leaves intact any positive reinforcement factors. As such, it should not be mistakenly regarded as a cure for opioid habituation. Such does not exist, nor likely ever will. Addiction is a synonym for devotion, and devotion to a habit is in any case hardly a
disease, pursuant to ordinary understanding and use of the term, irrespective of the possibility of medical management of drug habits. The nature and intensity ofthe opioid withdrawal syndrome, as well as its relative importance in sustaining habituation, has been exaggerated wildly in films (e.g.. The Man with the Golden Arm, Monkey on my Back) and literature (notably William Burroughs' Junkie and Naked Lunch). Burroughs' "algebra of need" is a satisfactory literary device, but as mathematics does not add up to real numbers. The physical withdrawal syndrome is not the sine qua non of addiction. Perhaps it is more fruitful to view opioid habituation as a sort of religious faith. Having once had sufficient experience, the opioid habitue comes to acquire a confirmed belief in an obdurate dogma of diminishing dose-response; supported by hard physical evidence (felt in the bones), as well as eyewitness-testimony (what all the experts and fellow users say). Having twice or thrice experienced total withdrawal from a state of physical dependency on opioids, there is likewise inculcated in the user a fervent belief in the inevitability of this pay-for-play purgatory: the more you take, the better you feel; and the longer you feel better, the worse you'll feel when you stop. These confirmed beliefs in inflexible dogmas, at times attested and reconfirmed every single day, are in my view keystones in the psychological arch buttressing opioid habituation. As Burroughs put it: "no good . . . no bueno . . . hustling myself (Burroughs 1959: 213). Physical dependence on opioids and the allied withdrawal syndrome are real and physiological, but psychological or psychophysical factors are at least as important in the long-term maintenance of opioid habituation. Banishing the spectre ofthe dread opioid withdrawal syndrome is in itself a major advance, but the real significance of these findings, at least for me, as a trained scientific researcher who approaches these matters in that spirit, is this: in a flash, as it were, a single ingestion-experiment (reducing the dose by 25%, with no reduction in intensity of effects) can suffice convincingly to refute perhaps years of daily evidence and supportive testimony for the dopers' dogma of diminishing dose-response; as, in turn, a single experience of asymptomatic and uneventful withdrawal can render the heretofore inevitable Sword of Damocles eminently forgettable. This is the crux of the case, but its meaning to a given habitu6 is a matter of conjecture. In my case, these dramatic refutations at once and forever altered my personal psychology regarding opioid habituation, something now not worthy of much personal thought or care. For another, however, a new dogma of play-anddon't-pay might simply conduce to increased indulgence. Moreover, what is being discussed here is oral ingestion of opioids, in which the euphoric reward is some 30 to 60 minutes removed from the act of ingestion. The closer is the temporal connection between ingestion-behavior and
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associated reward, the more habituating is that behavior (recall one can not become addicted to drugs per se, but rather to the habit of ingesting them; until the twentieth century, the substantive "addict" did not exist in English, and "addiction" was used with linguistic precision, viz., addiction to a habit of ingesting one or another drug, or to another behavior). In the case of intravenous drug injection, this reward delay is but a minute or so; following inhalation of alkaloidal free-base vapors, about 30 seconds merely. In this latter circumstance, ingestion-act and related reward become virtually contemporaneous, insofar as one begins to feel the rewarding "rush" even before exhaling. To inhale vapors of free-base cocaine is directly to confront crystalline craving. It is unclear, pending further investigation, whether picomolar naltrexone combined with injected or vaporized and inhaled opioids can block and reverse tolerance or obviate the withdrawal syndrome, as is the case with oral ingestion (although the animal research on which the present report is based involved induced dependency via injected morphine). One final point is more than significant. During the stepwise dose reduction in Experiment 1, very satisfactory euphoric effects were experienced for the first five days, although at the end of that period, my daily dose stood at 96 mg, or less than one-eighth of my habitual dosage! This is unheard of in stepwise withdrawal. Significantly, that dose, around 100 mg, constitutes the lowest dose that had sufficed to produce euphoric effects for me, when I had first used opioids some 30 years ago. This is to be expected, were one indeed undoing and readjusting stepwise the biochemical substrate of opioid tolerance, which appears to be the case. While astonishing at the time, on subsequent reflection this did not surprise me overmuch. There is every reason to anticipate such rapid homeostatic plasticity in an exquisitely sensitive and primary neural control mechanism, which mediates vital physiological parameters.
Obviation of Opioid Withdrawal Syndrome
such as setting and maintaining pain thresholds. Since physical tolerance can be acquired from a single opioid dose, it follows that a single dose could in principle diminish it. Certainly it is remarkable that one can reduce an opioid habit to one-eighth its former level over five days, while experiencing opioid euphoria from each successively diminished dose. This is a dramatic first I'd have thought next to impossible prior to having experienced it. NOTES 1. Anti-Mithridatism: Mithridates VI of Pontus (12063 BC), together with his infamous physician Kratevas, on the basis of human experimentation upon condemned convicts, who were poisoned, developed an all-purpose antidote to poisoning, which was named the mithridatium or mithridate. This was a type of theriac, and it happens that opium was a chief, and later practically the sole, ingredient in theriacs. Whereas a theriac was designed to prevent illness (perhaps as an immunostimulant), repeated small doses of toxins in the mithridatium were supposed to establish a progressive immunity to their toxicity. 2. Pain Therapeutics, Inc.; 250, E. Grand Street, Suite 70; San Francisco, CA, 94080. The company has already released preliminary data on animal testing of these two products: MorViva® in two formulations, both designated PTI-555 (morphine sulfate 3 mg/kg + naltrexone 0.3 ng/ kg; and morphine sulfate 3 mg/kg + naltrexone 3 ng/kg) and OxyTrex® likewise in two formulations, both designated PTI-801 (oxycodone 0.1 mg/kg + naltrexone 1 pg/ kg; oxycodone 0.1 mg/kg + naltrexone 1 ng/kg). Measuring tail-flick latency in female mice, MorViva® showed stronger analgesia and greater duration than 3 mg/kg morphine sulfate neat; whereas OxyTrex® showed stronger analgesia than 0.1 mg/kg oxycodone neat.
Beers, M.H. & Berkow, R. (Eds.) 1999. The Merck Manual of Diagnosis and Therapy. Whitehouse Station, New Jersey: Merck Research Laboratories. Burroughs, W.S. 1959. Naked Lunch. New York: Grove Press. Burroughs, W.S. 1953. Junkie. New York: Ace Books. Crain, S.M. & Shen, K.-F. 1996. United States Patent No. 5,580,876; issued 3 December. Supported by an extensive bibliography. Kolb. L. & Himmelsbach, C.K. 1938. Clinical studies ofdrug addiction. III. A critical review of withdrawal treatments with methods of evaluating abstinence syndromes. American Journal of Psychiatry 94: 759-97. Mamell, T. (Ed.) 1995. Drug Identification Bible, Second Edition. Denver, Colorado: Drug Identification Bible. Ott, J. 2001. Pharmafiopo-psychonautics: Human intranasal, sublingual, intrarectal, pulmonary and oral pharmacology of bufotenine. Journal of Psychoactive Drugs 33: 273-81. Ott, J. 1997. Pharmacophilia or the Natural Paradises. Vashon, Washington: Natural Products Co. Small, L.F.; Eddy, N.B.; Mosettig, E. & Himmelsbach, C.K. 1938. Studies on Drug Addiction, with Special Reference to Chemical Structure of Opium Derivatives and Allied Synthetic Substances and their Physiological Action. Supplement No. 138 to the Public Health Reports. Washington, D.C: U.S. Government Printing Office. Trujillo, K.A. & Akil, A. 1991. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85-7. Watkins, L.R.; Kinscheck, I.B. & Mayer, D.J. 1984. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science 224: 395-6.
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