Obviation of Opioid

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Obviation of Opioid WithdrawalSyndrome by Concomitant Administrationof Naltrexone in Microgram Doses:

Two Psychonautic Bioassays^Jonathan Ott*

Abstract Tw o psychonautic bioassays (self-experiments) in stepwise and abrupt cessation of long-term daily oral ingestion habits of 800 mg of codeine phosphate are presented. Concomitantadministration of minute doses (about 0.5 meg) of theopioid antagonist naltrexone with each dose ofcodeine was found in both cases to obviate the expected opioid withdrawal syndrome, resulting inasymptomatic and uneventful transitions from physical op ioid dependency states to exogenous opioid-free metabolism. These experiments are analyzed in the context of a conjectured, rapid, iterativereduction and complete elimination of opioid tolerance, once acquired. It was found thatcoadministration of naltrexone with codeine phosphate obviated the development of both toleranceand 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 biochemicalsubstrate 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, itsuggests 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 canbe reduced stepwise over a matter of days, w ith no symptoms of opioid withdrawal syndrome.Keyw ordsa ddiction, codeine, naltrexone, opioids, tolerance, withdrawal

Like progressive toleratice to their atialgesic atid eu-phoric effects, the well-ktiowti opioid withdrawal sytidromeis thought to be ati ineluctable sequel to cessatioti of ha-bitual use of opioids, at high etiough dosage and forsufficient duration. However, several classes of compotindsare known in animal ttiodels to ameliorate and even to

tTh e author is indebted to Richard H effem for valuable advice andconsultation.Partner, Entheobotanica, Solothum, Switzerland.Please ad dress correspondence and reprint requests to Jonathan Ott,Entheobotanica, K ronengasse, 11, Solothum CH -4502, S witzerland.

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prevent the development of opioid tolerance, and also toattenuate the allied withdrawal syndrome, a phenomenon Irecently dubbed "anti-Mithridatism"' (Ott 1997). Examplesof anti-Mithridatism are the use of dizocilpine , also knownas M K-80 1 (Trujillo & Akil 1991), and pro glum ide(Watkins, Kinscheck & Mayer 1984). Based likewise onanimal models, it has lately been reported that nano- andpicomolar doses of naltrexone, coadministered with opio-ids, could not merely enhance their analgesic potency, butattenuate the withdrawal syndrome occasioned by their

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Ott Obviation of Opioid Withdrawai Syndrome

withdrawal from dependent animals. This follows the in-triguing discovery that the m-opioid receptors that mediateanalgesia exist as two types on nociceptive neurons (pain-sensitive neurons): apart from the prototypical inhibitory|i-receptors, there is a much smaller population of excita-tory ^.-receptors , opioid binding to which produceshyperalgesia (Crain & Shen 1996). In this innovative tech-nique, which is currently undergoing clinical trials by PainTherapeutics , Inc. (using MorViva and OxyTrex),^minute doses of the potent opioid antagonist naltrexone (ca.1: 100,000 in relation to opioid doses, expressed as molarequivalents of base) apparently block preferentially thesehyperalgesic, excitatory m -receptors, and in effect "unm ask"the true analgesic potency of opioids.

Being a long-time (ca. 25 years) daily user of medici-nal opiates (chiefly mo rphine sulfate pe roral, up to 300 mg/day, and codeine phosphate peroral, up to 1.6 g/day), I amwell familiar with the opioid withdrawal syndrome, bestdetailed in human studies by the U.S. Public Health Ser-vice at the erstwbile federal "narcotics farm" prison inLexington, Kentucky (Kolb & Himmelsbach 1938; Smallet al. 1938). When I learned of this biphasic, mixed analge-sic/hyperalgesic activity of opioids in animals, I at onceresolved to ascertain whether it were operative in humanbeings. Using pharmaceutical codeine phosphate of knowndosage and unmixed with aspirin or other drugs, and stan-dard solutions of pharmaceutical naltrexone hydrochloride(Antaxone, which allowed precise oral or sublingual ap-plication of 0.5meg doses, expressed as naltrexone base), Ibegan their concomitant administration. At roughly a 1:100,000 (as molar equivalents) ratio of naltrexone base tocodeine base, peroral, there was approximately a 30% in-crease in potency, as assessed by subjective (euphoric)effects, in contrast to crude tests for analgesia in commonuse by pharm acologists, despite the fact that I was then tak-ing 800 mg/day code ine phosphate peroral, divided into fourdoses of 200 mg each. I assert that an experienced opioidhabitue, who knows dosage amounts precisely, is able tomake rather good subjective assessments of potencyamethadone-maintainee, for instance, would know soonenough if a reduced or enhanced dose had mistakenly beenadministered. So dramatic and incontrovertible was thispotentiation, that I at once reasoned it should follow that a25% reduction in codeine dosage cu m naltrexone would beperceived as being equipotent with my habitual dose ofcodeine neat. This proved to be a palpable hit: it was in-deed equipotent. This suggested that the biochemicalsubstrate of opioid tolerance (which remains as inscrutableas ever, despite exhaustive research) is amenable to phar-maco logical readjustm ent in real time , as it were . It followedinexorably, then, that in principle an opioid habitud couldstepwise rachet-down tolerance; indeed, reduce the dose tozero, absent the opioid withdrawal syndrome. This alsoproved to be true, as will be evident from my two self-experiments .

ETHICS OF SELF-EXPERIMENTIONWITH PSYCHOACTIVE DRUGS

In peer-review of this article, the issue of ethics wasraised: specifically regarding the fact that this research "wasnot conducted under the auspices of an Institutional Re-view Board" (IRB), nor a physicia n's supervision. In a prioarticle in this journal, I have already addressed the ethicadimensions of purportedly "objective" pharmacologicaresearch with animals, as opposed to "subjective" humanself-experimentation (Ott 2001). As far as the IRB is con-cerned, such does not apply here, insofar as the researchwas not conducted at any institution, nor involved any sub-ject other than the experimenter.

EXPERIMENT 1: MA Y-JUN E 2001I am the subject, then aged 52 and in good health. I

was taking daily 80 0 mg codeine pho sphate peroral as four200 mg doses (Perduretas), and had m aintained tbis habitfor over a year, at times taking 1.0-1.6 g codeine phos-phate daily. I resolved to reduce my habitual d ose stepwiseover 14 days, with tbree plateaus (where a given dose isrepeated a second day). I followed a valuable practice: eachdaily dose was taken a balf-bour later in tbe day, that is24.5 hours elapsed between doses (25 hours is probablybetter). As bas been known since De Quincey's day, it isunproblematic to reduce one's dose by one-balf, and sotbe day before com me ncing, I simply prescinded (or elimi-nated) two of my customary four doses, thus taking 400mg. Table 1 shows tbe reduction schedule. Each codeinedose was accompanied by 0.5 meg naltrexone base, ex-cepting Day 1, wben the dose was 1.0 meg.

I experienced only tbe slightest withdrawal symptomson Day 1 (neck and shoulder ten sion starting 1.5 hoursbefore dose time) and on Day 2 (similar tension two boursbefore dose time, and slight goose flesh 0.5 hours prior)This was likely due to an overly abrupt initial reduction indosage. Apart from tbis, I passed a completely asymptom-atic and uneventful witbdrawal, in the course of wbich Iate, slept and worked normally. Althougb tbere was some"clock-watcbing" up to Day 3, on Day 9 I forgot tbe timeand took my dose an hour late. Following merely 36 hoursof total abstinence (having been asym ptom atic for 13 daysand after 10 days at doses beneatb 10% of the habitual)on tbe morning of Day 15 and again that evening, I tooktwo 120 mg doses of codeine phosphate, wbich of coursegave good euphoric effects. Then on Day 16, 24 bours af-ter tbe second dose of co dei ne , I con duc ted analtrexone-challenge test, by taking 25 mg naltrexone per-oral, wbicb would bave precipitated withdrawal symptomsbad I somehow been mistaken in my appraisals, or had theprompt resumption of codeine intake for one day reestab-lished physical de penden ce. Althougb I could indeedperceive the "anti-opioid" nature of naltrexone, absolutely

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Day012345678910111213141516

TABLE 1Codeine-Withdrawal Reduction-Schedule (Experiment 1)

Dose400 mg160 mg144 mg120mg120mg96 mg80 mg80 mg64 mg48 mg48 mg40 mg32 mg24 mgOm g

240 mg

Total Reduction50%60%64%70%76%80%84%88%90%92%94%

100%

% Reduction50 %60 %10%17% Week 1: 800 mg20 %17%20 %25 %17% Week 2: 256 mg20%25 %

Naltrexone (25 mg) Challenge

no withdrawal symptoms supervened. Out of curiosity, overthe next 72 hours, I made six "codeine-challenges" ofnaltrexone. 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, per-haps 50% attenuated. At 72 hours, naltrexone blockade ofm-receptors had ceased, which agreed with my calculationsbased on data showing an approx imate four-hour tissue half-life for naltrexone.

EXPERIMENT 2: JUNE 2002I again maintained a habit of 800 mg/day codeine ph os-phate peroral for several months, always administering each200 mg dose of codeine with 1.0 m eg naltrexone orally orsublingually. Given the above self-experiment, it seemedlo me possible that not only might I develop no toleranceto codeine-effects, but that such a habit could abruptly beterminated w ithout occasioning any w ithdrawal syndrom e.In this case, I merely dropped my daily dose to 200 mgover three days by the simple exp edient of daily prescindingone of my habitual doses. On the fourth day and thence-forth until this writing two months later, I abstainedcompletely from codeine or other opioid analgesic. Al-though I felt weary on my first opiate-free day, I sleptnormally and experienced not the slightest trace of anyopioid withdrawal syndrome.

I might add parenthetically that throughout the courseof four daily doses of 200 mg codeine phosphate, solideuphoric effects followed each by some 30 minutes (thepills were crushed in a mortar and partially dissolved inhot water), suggesting tolerance was not developing. Onthe other hand, absent naltrexone, this is normal in my ex-periencedespite development of progressive tolerance,a controlled user who kno ws dose precisely can stabilize ata mid-level dose, experience pleasant, but not overwhelm-ing, opioid euphoria, and maintain that situation indefinitely.It is worth noting that exaggerated attention is focused onuncontrolled users with no idea of dosage, nor indeed pu-rity, much less identity, of their opioids. Meanwhile, theUnited States, with roughly 4% ofthe world's population,in 1994 consumed 700 tons or 50% of the world's licitopium p roduction , which is to say 13 times w orld per capitaconsumption (International Narcotics Control Board, cf.Marnell 1995). Most of this raw material for opiate phar-maceuticals is converted to codeine, much simply extractedand purified as morphine salts, some transformed to po-tent, artificial opiate derivatives like oxycodone andoxymorphone. Now, 700 tons of opium (even at a conser-vative 10% morphine), represents 70 tons of morphine (or70,000,000 g). Assuming a daily oral habit of 100 mg(which I can attest certainly leads to physical dep endency;vide also Burroughs 1959, 1953), 36.5 g per year wouldmaintain one "addict," and 70 tons in principle could

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support nearly two million such habits. This is certainly ahigher 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 orpersonal choice.

C O M M E N T A R YThe two experiments of opioid withdrawal described

hereco mpletely novel in my long experience with suchmay wel l represent the f i r s t repor ts ever of t ru lyasymptomatic withdrawal of opioids following long-estab-lished habituation to significant and multiple daily doses.While of course no comparison can be made to intravenousinjection of street heroin in terms of analgesic potency inhuman beings, 800 mg of codeine phosphate peroral isequivalent to 240 mg of morphine sulfate or 120 mg ofoxycodone hydrochloride peroral (Beers & Berkow 1999).What is being discussed here is the obviation, not of opioidhabituation per se, but of aspects of tolerance and physicaldependen ce, heretofore thought to follow like night, the dayof cessation of an opioid habit of such dosage-level andduration as to constitute so-called "addiction." The term"addiction" is used so loosely and tendentiously, and hasbeen subject to so many redefinitions and qualifications, asto render it too imprecise for scientific use. The physicalwithdrawal syndrome was once held to be the sine qua nonof addiction (Small et al. 1938) until a paradigm-shift oc-curred in the 1980s. Whereas prior to this , negativereinforcement (i.e., avoidance of the pain of withdrawal)had been held to be the primary motor of addiction, posi-tive reinforcement (rewarding effects) came to displace it,and today the drugs considered to have the highest "addic-t ive l iab i l i ty" are the s t imulants , notably cocaine,amphetamines and nicotine, the withdrawal of which fromhabitues occasions no physical withdrawal syndrome ofnote. Despite politically-inspired efforts to conjure acocainic withdrawal syndrome, in my long experience andbased on observations and interviews of more than 100habitues, nothing resembling the opioid withdrawal syn-drome accrues on cessation of habitual use, irrespective ofits duration and dosage-levels. The same is true for nico-tine, even after prolonged sublingual use exceeding 100 mg/day of nicotine free-base (this w ill be the subject of anothe rreport). "Mcofine-habituation" is often used carelessly todescribe "tobacco-smoking habituation." The so-called "to-bacco-smoking withdrawal-syndrome" does not appear tobe based on physical dependency on nicotine (present atlow, nonpsych oactive leve ls in comm ercial tobac co; ca. 1.0mg/cigarette). To obviate the physical withdrawal syndromeof opioids, while it perforce removes negative reinforce-ment aspects of the habit, nonetheless leaves intact anypositive reinforcement factors. As such, it should not bemistakenly regarded as a cure for opioid habituation. Suchdoes not exist, nor likely ever will. Addiction is a synonymfor devotion, and devotion to a habit is in any case hardly a

disease, pursuant to ordinary understanding and use of theterm, irrespective of the possibility of medical manage-ment of drug habits.

The nature and intensity ofthe opioid withdrawal syn-drome, as well as its relative importance in sustaininghabituation, has been exaggerated wildly in films (e.g.. Th eMan with the Golden Arm, Monkey on my Back) and lit-erature (notably William Burroughs' Junkie and NakedLunch). Burroughs' "algebra of need" is a satisfactory lit-erary device, but as mathematics does not add up to realnum bers. The physical withdrawal syndrome is not the sinequa non of addiction . Perhap s it is more fruitful to viewopioid habituation as a sort of religious faith. Having oncehad sufficient experience, the opioid habitue comes to ac-quire a conf i rmed bel ief in an obdura te dogma ofdiminishing dose-response; supported by hard physicalevidence (felt in the bones), as well as eyewitness-testi-mony (what all the experts and fellow users say). Havingtwice or thrice experienced total withdrawal from a stateof physical dependency on opioids, there is likewise in-culcated in the user a fervent belief in the inevitability ofthis pay-for-play purgatory: the more you take, the betteryou feel; and the longer you feel better, the worse you'llfeel when you stop. These confirmed beliefs in inflexibledogm as, at times attested and reconfirmed every single day,are in my view keystones in the psychological arch but-tressing opioid habituation. As Burroughs put it: "nogood . . . no bueno . . . hustling m ys el f (Burroughs 1959:213). Physical dependence on opioids and the allied with-d raw al s yndrome a re r ea l and phys io log ica l , bu tpsychological or psychophysical factors are at least asimportant in the long-term maintenance of opioid habitua-tion.

Banishing the spectre ofthe dread opioid withdrawalsyndrome is in itself a major advance, but the real signifi-cance of these find ings, at least for me, as a trained scientificresearcher who approaches these matters in that spirit, isthis: in a flash, as it were, a single ingestion-experiment(reducing the dose by 25%, with no reduction in intensityof effects) c an suffice co nvincing ly to refute perhaps yearsof daily evidence and supportive testimony for the dopers'dogma of diminishing dose-response; as, in turn, a singleexperience of asymptomatic and uneventful withdrawal canrender the heretofore inevitable Sword of Dam ocles emi-nently forgettable. This is the crux of the case, but itsmeaning to a given habitu6 is a matter of conjecture. Inmy case, these dramatic refutations at once and foreveraltered my personal psychology regarding opioid habitua-tion, something now not worthy of much personal thoughtor care. For another, however, a new dogma of play-and-don't-pay might simply conduce to increased indulgence.

Moreover, what is being discussed here is oral inges-tion of opioids, in which the euphoric reward is some 30to 60 minutes removed from the act of ingestion. The closeris the temporal connection betw een ingestion-behav ior and

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associated reward, the more habituating is that behavior(recall one can not become addicted to drugs per se, butrather to the habit of ingesting them; until the twentiethcentury, 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 toanother behavior). In the case of intravenous drug injec-tion, this reward delay is but a minute or so; followinginhalation of alkaloidal free-base vapors, about 30 secondsmerely. In this latter circumstance, ingestion-act and re-lated reward become virtually contemporaneous, insofaras one begins to feel the rewarding "rush " even before ex-haling. To inhale vapors of free-base cocaine is directly toconfront crystalline craving. It is unclear, pending furtherinvestigation, whether picomolar naltrexone combined withinjected or vaporized and inhaled opioids can block andreverse tolerance or obviate the withdrawal syndrome, asis the case with oral ingestion (although the animal researchon which the present report is based involved induced de-pendency via injected morphine).

One final point is more than significant. During thestepwise dose reduction in Experiment 1, very satisfactoryeuphoric effects were experienced for the first five days,although at the end of that period, my daily dose stood at96 mg, or less than o ne-eighth of my habitual dosage! Thisis unheard of in stepwise withdrawal. Significantly, thatdose, around 100 mg, constitutes the lowest dose that hadsufficed to produce euphoric effects for me, when I hadfirst used opioids some 30 years ago. This is to be expected,were one indeed undoing and readjusting stepwise the bio-chemical substrate of opioid tolerance, which appears tobe the case. While astonishing at the time, on subsequentreflection this did not surprise me o vermuch . There is ev-ery reason to anticipate such rapid homeostatic plasticityin an exquisitely sensitive and primary neural controlmechanism, which mediates vital physiological parameters.

such as setting and maintaining pain thresholds. Sincephysical tolerance can be acquired from a single opioiddose, it follows that a single dose could in principle dimin-ish it. Certainly it is remarkable that one can reduce anopioid habit to one-eighth its former level over five days,while experiencing opioid euphoria from each successivelydiminished dose. This is a dramatic first I'd have thoughtnext to impossible prior to having experienced it.N O T E S

1. Anti-Mithridatism: Mithridates VI of Pontus (120-63 BC ), together with his infamous physician Kratevas, onthe basis of human experimen tation upon condemned con-victs, who were poisoned, develop ed an all-purpose antidoteto poisoning, which was named the mithridatium or mith-ridate. This was a type of theriac, and it happen s that opiumwas a chief, and later practically the sole, ingredient intheriacs. Wh ereas a theriac was designed to prevent illness(perhaps as an imm unostimu lant), repeated small doses oftoxins in the mithridatium were supposed to establish a pro-gressive immun ity to their toxicity.

2. Pain Therapeu tics, Inc.; 250, E. Grand Street, Suite70; San Francisco, CA, 94080. The company has alreadyreleased preliminary data on animal testing of these twoproducts: MorViva in two form ulations, both designatedPTI-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 desig-nated PTI-801 (oxyco done 0.1 m g/kg + naltrexone 1 pg/kg ; oxycod one 0.1 mg/kg + naltrexone 1 ng/kg). Measur-ing tail-flick latency in female mice, MorViva showedstronger analgesia and greater duration than 3 mg/kg mor-phine sulfate neat; whereas OxyTrex showed strongeranalgesia than 0.1 mg/kg oxycodone neat.

REFERENCES

Beers, M.H. & Berkow, R. (Eds.) 1999. The Merck Manual of Diagnosisand Therapy. Whitehouse Station, New Jersey: Merck ResearchLaboratories.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 ofevaluating abstinence syndromes. American Journal of Psychiatry94 : 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. Studieson Drug Addiction, with Special Reference to Chemical Structureof Opium Derivatives and Allied Synthetic Substances and theirPhysiological Action. Supplement No. 138 to the Public HealthReports. Washington, D. C: U.S. Government Printing Office.Trujillo, K.A. & Akil, A. 1991. Inhibition of morphine tolerance anddependence by the NMDA receptor antagonist MK-801. Science2 5 1 : 8 5 - 7 .Watkins, L.R.; Kinscheck, I.B. & Mayer, D.J. 1984. Potentiation of opiateanalgesia and apparent reversal of morphine tolerance byproglumide. Science 224: 395-6.

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Obviation of Opioid