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Obviation of Opioid Withdrawal Syndronte by Concomitant Adntinistration of Naltrexone in Microgrant Doses: Two Psychonautic Bioassayst

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Obviation of Opioid Withdrawal Syndronte by Concomitant Adntinistration of Naltrexone in Microgrant Doses: Two Psychonautic Bioassayst Obviation of Opioid Withdrawal Syndronte by Concomitant Adntinistration of Naltrexone in Microgrant Doses: Two Psychonautic Bioassayst Jonathan Ott* Abstract-Two psychonautic bioassays (self-experiments) in stepwise and abrupt cessation of long­ term 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 opioid­ free 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 tolerance to their analgesic and eu­ prevent the development of opioid tolerance, and also to phoric effects, the well-known opioid withdrawal syndrome attenuate the allied withdrawal syndrome, a phenomenon I is thought to be an ineluctable sequel to cessation of ha­ recently dubbed "anti-Mithridatism" 1 (Ott 1997). Examples bitual use of opioids, at high enough dosage and for of anti-Mithridatism are the use of dizocilpine, also known sufficient duration. However, several classes of compounds as MK-801 (Trujillo & Akil 1991), and proglumide are known in animal models to ameliorate and even to (Watkins, Kinscheck & Mayer 1984). Based likewise on tThe author is indebted to RichardHef fern for valuable advice and animal models, it has lately been reported that nano- and consultation. picomolar doses of naltrexone, coadministered with opio­ *Partner, Entheobotanica, Solothurn, Switzerland. ids, could not merely enhance their analgesic potency, but Please address correspondence and reprint requests to Jonathan Ott, Entheobotanica, Kronengasse, II, Solothurn CH-4502, Switzerland. attenuate the withdrawal syndrome occasioned by their Joumal of Psychoactive Drugs 101 Volume 38 (I}, March 2006 Ott Obviation of Opioid Withdrawal Syndrome withdrawal from dependent animals. This follows the in­ ETHICS OF SELF-EXPERIMENTION triguing discovery that the m-opioid receptors that mediate WITH PSYCHOACTIVE DRUGS analgesia exist as two types on nociceptive neurons (pain­ sensitive neurons): apart from the prototypical inhibitory In peer-review of this article, the issue of ethics was 11-receptors, there is a much smaller population of excita­ raised: specifically regarding the fact that this research "was tory IJ.-receptors, opioid binding to which produces not conducted under the auspices of an Institutional Re­ hyperalgesia (Crain & Shen 1996). In this innovative tech­ view Board" (IRB), nor a physician's supervision. In a prior nique, which is currently undergoing clinical trials by Pain article in this journal, I have already addressed the ethical Therapeutics, Inc. (using MorViva® and OxyTrex®),2 dimensions of purportedly "objective" pharmacological minute doses of the potent opioid antagonist naltrexone (ca. research with animals, as opposed to "subjective" human I: I 00,000 in relation to opioid doses, expressed as molar self-experimentation (Ott 200 I). As far as the IRB is con­ equivalents of base) apparently block preferentially these cerned, such does not apply here, insofar as the research hyperalgesic, excitatory m-receptors, and in effect "unmask" was not conducted at any institution, nor involved any sub­ the true analgesic potency of opioids. ject other than the experimenter. Being a long-time (ca. 25 years) daily user of medici­ nal opiates (chiefly morphine sulfate peroral, up to 300 mg/ EXPERIMENT 1: MAY-JUNE 2001 day, and codeine phosphate peroral, up to 1.6 g/day), I am well familiar with the opioid withdrawal syndrome, best I am the subject, then aged 52 and in good health. I detailed in human studies by the U.S. Public Health Ser­ was taking daily 800 mg codeine phosphate peroral as fo ur vice at the erstwhile federal "narcotics farm" prison in 200 mg doses (Perduretas®), and had maintained this habit Lexington, Kentucky (Kolb & Himmelsbach 1938; Small for over a year, at times taking 1.0- 1.6 g codeine phos­ et al. 1938). When I learned of this biphasic, mixed analge­ phate daily. I resolved to reduce my habitual dose stepwise sic/hyperalgesic activity of opioids in animals, I at once over 14 days, with three plateaus (where a given dose is resolved to ascertain whether it were operative in human repeated a second day). I fo llowed a valuable practice: each beings. Using pharmaceutical codeine phosphate of known daily dose was taken a half-hour later in the day, that is, dosage and unmixed with aspirin or other drugs, and stan­ 24.5 hours elapsed between doses (25 hours is probably dard solutions of pharmaceutical naltrexone hydrochloride better). As has been known since De Quincey's day, it is (Antaxone®, which allowed precise oral or sublingual ap­ unproblematic to reduce one's dose by one-half, and so plication of 0.5 meg doses, expressed as naltrexone base), I the day before commencing, I simply prescinded (or elimi­ began their concomitant administration. At roughly a I: nated) two of my customary four doses, thus taking 400 I 00,000 (as molar equivalents) ratio of naltrexone base to mg. Table I shows the reduction schedule. Each codeine codeine base, peroral, there was approximately a 30% in­ dose was accompanied by 0.5 meg naltrexone base, ex­ crease in potency, as assessed by subjective (euphoric) cepting Day I, when the dose was 1.0 meg. effects, in contrast to crude tests for analgesia in common I experienced only the slightest withdrawal symptoms use by pharmacologists, despite the fact that I was then tak­ on Day I (neck and shoulder tension starting 1.5 hours ing 800 mg/day codeine phosphate peroral, divided into four before dose time) and on Day 2 (similar tension two hours doses of 200 mg each. I assert that an experienced opioid before dose time, and slight goose flesh 0.5 hours prior). habitue, who knows dosage amounts precisely, is able to This was likely due to an overly abrupt initial reduction in make rather good subjective assessments of potency-a dosage. Apart from this, I passed a completely asymptom­ methadone-maintainee, for instance, would know soon atic and uneventful withdrawal, in the course of which I enough if a reduced or enhanced dose had mistakenly been ate, slept and worked normally. Although there was some administered. So dramatic and incontrovertible was this "clock-watching" up to Day 3, on Day 9 I forgot the time potentiation, that I at once reasoned it should follow that a and took my dose an hour late. Following merely 36 hours 25% reduction in codeine dosage cum naltrexone would be of total abstinence (having been asymptomatic for 13 days perceived as being equipotent with my habitual dose of and after 10 days at doses beneath 10% of the habitual), codeine neat. This proved to be a palpable hit: it was in­ on the morning of Day 15 and again that evening, I took deed equipotent. This suggested that the biochemical two 120 mg doses of codeine phosphate, which of course substrate of opioid tolerance (which remains as inscrutable gave good euphoric effects. Then on Day 16, 24 hours af­ as ever, despite exhaustive research) is amenable to phar­ ter the second dose of codeine, I conducted a macological readjustment in real time, as it were. It followed naltrexone-challenge test, by taking 25 mg naltrexone per­ inexorably, then, that in principle an opioid habitue could oral, which would have precipitated withdrawal symptoms stepwise rachet-down tolerance; indeed, reduce the dose to had I somehow been mistaken in my appraisals, or had the zero, absent the opioid withdrawal syndrome. This also prompt resumption of codeine intake for one day reestab­ proved to be true, as will be evident from my two self­ lished physical dependence. Although I could indeed experiments. perceive the "anti-opioid" nature of naltrexone, absolutely Journalof Psychoactive Drugs 102 Volume 38 (I), March 2006 Ott Obviation of Opioid Withdrawal Syndrome TABLE 1 Codeine-Withdrawal Reduction-Schedule (Experiment 1) Day Dose Total Reduction %Reduction 0 400 rng 50% 50% I 160 rng 60% 60% 2 144 rng 64% 10% 3 120 rng 70% 17% 4 120 rng Week I : 800 rng 5 96 rng 76% 20% 6 80 rng 80% 17% 7 80 rng 8 64 rng 84% 20% 9 48 rng 88% 25% 10 48 rng II 40 rng 90% 17% Week 2: 256 rng 12 32 rng 92% 20% 13 24 rng 94% 25% 14 0 rng 100% 15 240 rng 16 Naltrexone (25 rng)C hallenge no withdrawal symptoms supervened. Out of curiosity, over I might add parenthetically that throughout the course the next 72 hours, I made six "codeine-challenges" of of four daily doses of 200 mg codeine phosphate, solid naltrexone. Doses of 160 mg codeine phosphate at two, euphoric effects followed each by some 30 minutes (the three, 24, 38, 64 and 72 hours post-naltrexone were taken. pills were crushed in a mortar and partially dissolved in Not until 64 hours was any opioid effect perceived, per­ hot water), suggesting tolerance was not developing.
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