Tai kang ning for withdrawal

Herbal Medicines for the Management of Opioid Addiction Safe and Effective Alternatives to Conventional Pharmacotherapy?

Jeanine Ward,1 Christopher Rosenbaum,1 Christina Hernon,1 Christopher R. McCurdy2 and Edward W. Boyer1

1 Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts

Medical School, Worcester, MA, USA

2 Department of Medicinal Chemistry, Laboratory for Applied Drug Design and Synthesis, School of

Pharmacy, University of Mississippi, University, MS, USA

Abstract Striking increases in the abuse of opioids have expanded the need for pharmacotherapeutic interventions. The obstacles that confront effective treatment of opioid addiction – shortage of treatment professionals, stigma associated with treatment and the ability to maintain abstinence – have led to increased interest in alternative treatment strategies among both treatment providers and patients alike. Herbal products for opioid addiction and withdrawal, such as kratom and specific Chinese herbal medications such as WeiniCom, can complement existing treatments. Unfortunately, herbal treatments, while offering some advantages over existing evidence-based pharmacotherapies, have poorly described pharmacokinetics, a lack of sup- portive data derived from well controlled clinical trials, and severe toxicity, the cause for which remains poorly defined. Herbal products, therefore, re- quire greater additional testing in rigorous clinical trials before they can ex- pect widespread acceptance in the management of opioid addiction.

1. Introduction

Striking increases in the abuse of opioids have been observed over the last decade in the US, Eastern Europe, China and the Middle East.[1-3]

As rates of abuse and addiction have grown, the need for pharmacotherapeutic interventions has increased as well. Unfortunately, obstacles such as shortages of treatment centres and ad- dictionologists inhibit the delivery of evidence- based pharmacotherapies such as methadone and coformulated buprenorphine/naloxone in many locations.[3,4] In addition, there are high rates of

relapse associated with conventional interven- tions for opioid addiction. Finally, the stigma of receiving daily opioid replacement therapy in pub- lic venues such as methadone clinics may prevent some from seeking treatment in the first place.

The limitations of currently available conven- tional pharmacotherapies for opioid addiction may compel some individuals to use therapies that are more easily obtainable, perceived as having longer-lasting effects, and/or greater social accept- ability. As a result, interest in alternative treat- ment strategies for opioid addiction has increased among both treatment providers and patients

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alike.[5,6] Formulations of the more recognized alternative interventions, kratom and ibogaine, are derived from herbal material, but a number of Asian remedies used in the management of opioid abstinence syndromes incorporate animal and mineral materials as well. This review will de- scribe the pharmacology, toxicology and efficacy of herbal-based interventions, as well as assess potential risks to users. To identify the material synthesized in this review, we conducted initial searches of the English language literature using PubMed and Google Scholar databases. We did not restrict our search results by date. Results from these primary searches served as starting points for secondary searches related to specific topical matter for inclusion in the review. Although we relied upon peer-reviewed primary literature as sources for medical and scientific data, we cited anecdotal publications describing historical events related to clandestine treatments.

2. Kratom

Kratom (Mitragynia speciosa Korth) is a tree found in Southeast Asia that contains medici- nally relevant alkaloids known as mitragynines within its leaves.[7-9] The ability of the plant to produce these compounds is highly dependent on geography; plants growing in Southeast Asia elaborate mitragynines, but those grown elsewhere, even in tropical greenhouses, do not. Kratom leaves have traditionally been used as a substitute for opium or to treat withdrawal, as well as for their stimulant effects.[10] Moreover, Thai villagers use extracts of kratom leaves as a medicine to treat cough, diarrhoea and musculoskeletal pain.[8,10]

Ingestion by chewing, smoking, brewing into a tea, or swallowing a tarlike solid that has been extracted and reduced from the leaves are typical modes of administration.[7]

The predominant alkaloid isolated from kratom extracts is mitragynine; a minor component is 7-hydroxymitragynine, an oxidized congener.[8]

These compounds appear to be responsible for the analgesic effects of kratom through opioid receptor binding in vivo and in vitro.[11] Animal studies have demonstrated that the antinociceptive activity of mitragynine in the tail-pinch and hot-

plate tests is completed abolished by the pure opioid receptor antagonist naloxone.[12] Re- petitive administration of 7-hydroxymitragynine produces tachyphylaxis as well as cross-tolerance to morphine.[10] Furthermore, administration of naloxone to 7-hydroxymitragynine- and mor- phine-dependent rats produces abstinence symp- toms of comparable intensity.[13] Moreover, the chemical structure of the mitragynines also in- corporates the tryptamine nucleus, which may be responsible for the observed activity of the mol- ecules in the serotonin and adrenergic systems.[8]

The mitragynines, however, have a novel structural scaffold for opioid receptor affinity and activity.[8,14]

For example, both molecules contain the amino functionality and the phenolic moiety common to all opioid-based ligands.[8,15] Interestingly, based on the current understanding of the structure- activity relationships for the mitragynines, the phenolic methyl ether is more potent in analgesic paradigms.[11] This is in contrast to morphine where methylation of the phenol moieties (to produce codeine) reduces analgesic potency; for morphinan-based ligands, the phenolic hydro- gen provides critical interactivity with the opioid receptors.[16]

The pharmacokinetics of kratom in humans are poorly described; for example, the volume of distribution, half-life, protein binding, metabolism and elimination in humans are unknown. Clinical effects appear to be dose dependent.[7,17,18] In small amounts, manual labourers use kratom for its stimulant effects so that they may work in harsh conditions.[17,18] With larger doses, the euphoric effects of kratom are the basis for its use as a re- placement therapy for opium among addicts.[17,18]

Clinical effects of kratom mimic those of a m-opioid receptor agonist.[19] As early as 1897, kratom was recognized as an analgesic, antitussive, antidiarrhoeal and as a remedy for opium with- drawal. To date, however, no formal clinical trials have studied the efficacy and safety of kratom in the treatment of opioid addiction. Adverse effects from kratom are limited. Kratom use does not appear to be associated with the emesis that commonly accompanies opioid use. Interestingly, respiratory depression following kratom admin- istration has not been observed in either humans

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or in animal toxicity studies; even in rats that received high oral doses of mitragynine (up to 807mg/kg), respiratory depression did not occur.[20] Similarly, no evidence of respiratory depression was observed in mice at oral doses up to 920mg/kg of mitragynine.[20] In humans, generalized tonic- clonic seizure activity has been documented in at least two cases; neither individual had a history of seizure disorder nor was taking a pro-convulsant substance.[19,21] Chronic use of kratom has been associated with anorexia, weight loss, constipation and hyperpigmentation of the face.[9] An absti- nence syndrome similar to mild opioid withdrawal is characterized by rhinorrhoea, insomnia, lacri- mation, lethargy, myalgias, arthralgias and my- oclonus.[9] Although confined to anecdotal reports, a relatively mild rhinorrhoea has been the leading complaint of individuals suffering withdrawal fol- lowing rapid cessation of kratom use.[19]

Despite a paucity of pharmacokinetic, phar- macodynamic and toxicological data, kratom appears to enjoy widespread use among specific populations.[19,22] An ethnographic study has ex- amined website postings generated by individuals who self-treat chronic pain with opioid analgesics purchased from online pharmacies.[22] Striking increases in the number of posts generated by the study population that identified kratom as a highly effective method for treating opioid with- drawal and promoting abstinence from prescrip- tion opioid analgesics were seen over a 12-month study period.[22] In addition, case report-level data have reported the use by an individual of kratom as an effective replacement therapy for parenteral hydromorphone abuse.[19] Formal epidemiologi- cal data describing kratom use in the general population are lacking, but the number of web- sites that sell kratom – sometimes in kilogram quantities – suggests the popularity of the herbal product.[22]

While kratom may have medicinal uses, it also carries some abuse liability. Although unsched- uled in the US, kratom has been criminalized in a number of countries around the Pacific Rim, in- cluding Australia.[7] Compulsive use of kratom in a number of distinct populations, including injec- tion opioid abusers and individuals with chronic pain who self-prescribe opioid analgesics, is a well

described phenomenon.[19,22] Moreover, reports that students at some college campuses congregate to drink decoctions of kratom at ‘tea parties’, as well as the sale of kratom in bars, suggest its re- creational use may be growing.[23,24] For popu- lations who are too young to legally ingest ethanol, kratom may be a viable option to drinking in bars and may be a precursor to problematic opioid use.[23]

3. Ibogaine

Ibogaine is an indole alkaloid hallucinogen derived from the root bark of the African shrub Tabernanthe iboga.[25] Among indigenous peoples, ibogaine plays an integral role in ethnoreligious ceremonies where it induces hallucinations of protracted duration.[25] The hallucinogenic effect of ibogaine eventually led to recreational use, and in the early 1960s a young heroin addict experi- menting with ibogaine claimed that he felt no opioid craving after experiencing potent ibogaine- triggered hallucinations.[26] A group of self-treating heroin addicts reported the same outcome fol- lowing ibogaine use, leading to a small number of uncontrolled studies among opioid and cocaine abusers that have led some investigators to attri- bute substantial curative powers to ibogaine.[26]

Of even greater interest has been the proponents’ claim that ibogaine-mediated detoxification from opioids was associated with dramatically lower rates of relapse than conventional therapy.[26]

Unfortunately, the wealth of animal data direct- ed toward establishing the neurochemical basis of the putative anti-addiction effects of ibogaine has failed to overcome persistent concerns about the safety of the drug.[27,28] Consequently, outcomes from ibogaine-based treatment of opioid addic- tion are poorly defined because the drug has yet to be entered into rigorous clinical trials. At pre- sent, ibogaine carries a US Drug Enforcement Administration Schedule I classification and is deemed to have no clinical value.[28,29]

Comprehensive pharmacological data for oral administration of ibogaine are lacking. Ibogaine is a highly lipophilic molecule that is absorbed following oral, mucosal and intraperitoneal admin- istration. Ibogaine undergoes extensive first-pass

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metabolism.[25] Demethylation by cytochrome P450 (CYP)2D6 to noribogaine occurs in the gut and liver; after absorption from the gastro- intestinal tract, ibogaine distributes to tissues ac- cording to a two-compartment model. Ibogaine and noribogaine distribute to the spleen, liver, brain and lung; both drugs cross the blood-brain barrier and are secreted in bile.[30] Estimated a and b elimination half-lives of ibogaine are ap- proximately 7.3 minutes and 3.3 hours, respec- tively. Drug clearance rates are calculated at 5.6 L/hours.[31]

The exact neurochemical mechanisms under- lying the putative anti-addictive properties of ibogaine have not been elucidated but likely in- volve modulation of multiple neurotransmitter systems.[25] Ibogaine agonizes the m- and k-opioid receptors, although binding affinity is dependent on experimental technique; ibogaine also antag- onizes glutamate NMDA, as well as a3b4 nico- tinic, receptor sites.[32-39] This observation has led to the hypothesis that the anti-addictive effects of ibogaine may arise from complex intracellular signalling cascades that reset neuronal function and eliminate drug craving.[40,41] Unfortunately, this hypothesis awaits further investigation.

Although ibogaine has been used to treat the compulsive use of cocaine, methamphetamine, ethanol and other drugs, its greatest recogni- tion is for the management of opioid addiction. Only a handful of cases describing treatment outcomes, however, have been published despite nearly 50 years of experience using ibogaine for opioid abuse.[25] Moreover, the quality of the methodology described in these publications is frequently substandard, with the studies being poorly controlled, enrolling small numbers of participants and with often short durations of evaluation.[26,42-45] One publication described the treatment of 33 patients undergoing acute opioid withdrawal with nonstandardized ibogaine doses over a 31-year period; participants were followed for up to 72 hours after ibogaine treatment, a period so short that the major reported finding, absence of drug-seeking behaviour, is almost meaning- less.[43] Another study conducted by ‘a loosely-knit organization’ of an ‘Amsterdam squatter commu- nity’ described administration of nonstandardized

ibogaine doses to seven patients to treat opioid withdrawal symptoms.[42] Of these individuals, three used heroin during the 24-hour treatment period or immediately thereafter; 71% of partici- pants relapsed to opioid abuse within 3 weeks of treatment.[42] These results support the central finding of the study that ibogaine induces an in- terruption in heroin use, although the benefit of ibogaine is unclear if recipients relapse to heroin use during a treatment period of approximately 24 hours in length. In addition, an open-label study conducted at a private detoxification facil- ity in the Virgin Islands involved administration of fixed doses of ibogaine to 27 cocaine- and heroin-dependent individuals who were followed for up to 1 month.[45] Unfortunately, the total number of heroin-dependent patients, the time from last use of heroin and the number of partic- ipants completing treatment was not reported in this publication.[45] These shortcomings, coupled with the observation that expensive treatments often entice patients to distort the benefits of the intervention, raise questions about the extent to which any beneficial effect was realized.[46] No controlled trials using ibogaine have been pub- lished in the peer-reviewed literature.

Because ibogaine is most commonly adminis- tered in unconventional settings, formal data on the clinical and adverse effects of the drug are lacking.[47] Clinical findings associated with ibo- gaine ingestion include profound vomiting for many hours, sometimes longer than 1 day. The most prominent feature of ibogaine use, open- and closed-eye hallucinations, occurs at oral doses of greater than 200–300 mg.[42] Above this dosage range, ibogaine has been associated with hallucina- tions that may persist for up to 36–48 hours.[42,48,49]

Cerebellar dysfunction, including ataxia, tremor and nystagmus, is commonly observed and has an onset within 2–4 hours of drug administration. These signs may resolve within 12 hours of use.[49]

Individuals ingesting ibogaine have also reported muscle pain and soreness that persist beyond res- olution of the neuropsychiatric effects.[47]

The most feared complication of both ‘ther- apeutic’ and exploratory ibogaine use remains sudden death, most likely due to torsades de pointes arising from prolongation of the QT interval.

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One patient who survived ventricular dysrhyth- mias following ibogaine administration had dra- matic prolongation of the QT interval to 616msec when corrected for heart rate.[50] Two features of this patient’s clinical course are notable. First, the QT interval was unresponsive to the standard intervention of rapid electrolyte correction.[50]

Second, the QT interval remained prolonged for a protracted period, normalizing during the second hospital day.[50] This derangement in cardiac rhythm may not be unique to this patient. At least 11 sudden deaths have been associated with ibo- gaine use, but in each case, the cause of death could not be determined despite autopsy.[50,51] Despite extensive investigations using animal models into the neurochemical properties of ibogaine, little effort has been directed toward understanding the basis of its cardiotoxicity.[52]

4. Chinese Herbal Remedies

Opioid abuse and addiction have been a pub- lic health hazard in China for much of the last 200 years.[3] Governmental policies enacted in the 1950s curtailed opioid abuse, but economic re- forms of the 1980s led to a widespread resurgence of heroin addiction.[3] To confront the growing problem of drug addiction, the Chinese government has initiated pharmacotherapy programmes based on Western addiction treatment protocols.[3] Un- fortunately, the predominant treatment for opioid addiction is short-term detoxification with metha- done or buprenorphine at compulsory reeducation- through-work centres.[3] These programmes have faced great difficulties. Treatment centres are un- derfunded, and because patients undergo forced detoxification, they have high rates of relapse and low rates of recovery.[3] Finally, many opioid ad- dicts live in rural areas, where the reach of treat- ment programmes is limited.[3]

Traditional Chinese medicines have therefore received considerable interest as potentially more acceptable and less costly alternatives to standard pharmacotherapy. The Chinese State Food and Drug Administration has approved at least ten herbal-based products for the treatment of opioid withdrawal, with several more in clinical trials.[3]

Although Asian herbal remedies are often mix-

tures of plant matter, animal material and, in some cases, minerals or even toxic metals, the use of specific components in these complex mixtures as treatment for opioid withdrawal is supported by preclinical and clinical data.[53,54]

Corydolis yanhusuo is a herbal analgesic with sedative, hypnotic and antihypertensive proper- ties.[55] The active component, the natural pro- duct levotetrahydropalmatine (l-THP), inhibits in a murine model the locomotor hyperactivity induced by oxycodone.[56] In addition, treatment with l-THP can attenuate morphine-induced with- drawal syndromes and conditioned place pref- erence in mice.[57] These promising preclinical findings have triggered clinical investigations of l-THP. In a randomized, double-blind, placebo- controlled clinical trial, l-THP was administered to 120 heroin addicts over a 4-week period.[58]

Although l-THP effectively reduced opioid crav- ing, withdrawal syndromes and relapse rates in heroin-dependent patients, several features of this trial deserve mention.[58] First, all study par- ticipants had completed a 7-day detoxification period before enrolment in the study; virtually none, therefore, were likely to have been in acute withdrawal.[58] Second, of the 59 participants ran- domized to the l-THP group, only 44 ‘survived’ 2 of the 4 weeks of treatment whereas 59 of 61 participants who received placebo completed 2 of 4 weeks of treatment.[58] Third, the authors never state the number of participants in either group who completed the 4-week treatment period.[58]

Less than half of the l-THP-treated individuals who remained in the study at 2 weeks remained abstinent at 3 months; any beneficial outcomes, therefore, could have been driven by increased motivation to overcome addiction in a subset of the treatment population as much as from the effect of l-THP.[58]

Ginseng is another botanical commonly used in Chinese traditional remedies.[53] Two major types of ginseng exist, Panax ginseng (Asian gin- seng) and Panax quinquefolium (American gin- seng). The main active natural products in Panax ginseng are called ginsenosides, of which more than 20 have been characterized.[59] Ginsenosides have putative effects on the CNS and cardiovascular system, and may alter metabolism and immune

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function.[60] Panax ginseng attenuates the phys- iological effects of drugs of abuse including morphine in pre-clinical studies.[61] A multicentre clinical trial found that Radix ginseng (the root of Panax ginseng) was safe and effective for the treat- ment of moderate-to-severe acute heroin with- drawal.[62] In this double-blind study, 212 heroin addicts were randomized to treatment with either the ginseng herbal mixture or to lofexidine over a 10-day period.[62] The investigators found that the herbal mixture was as effective as lofexidine at alleviating the symptoms of opioid withdrawal, with patients reporting only gradual improvement in symptomatology over the study period.[62]

Unfortunately, lofexadine is minimally effective at treating acute opioid withdrawal, and the study design did not incorporate a placebo arm.[62] It is therefore possible that what was observed in the patients was untreated opioid withdrawal, the natural history of which is improvement over time. Significant adverse effects included eleva- tions of liver transaminases, but because Chinese herbal mixtures are manufactured with little reg- ulatory oversight, the specific cause of hepatic injury cannot be ascribed.[62,63]

The active chemical in Panax quinquefolium, not found in Panax ginseng, is pseudoginsenoside- F11 (PF11), a saponin.[59] Panax quinquefolium, especially PF11, exerts distinct effects following morphine administration. PF11 attenuates mem- ory impairment in the Morris water maze test, analgesia measured by tail pinch, locomotor sen- sitization and, at higher doses, the expression of conditioned place preference.[64] Neurochemically, PF11 antagonizes opioid receptor signalling and decreases the concentrations of dopamine and its metabolites in the brain of test animals treated with morphine.[65,66] While these findings suggest that formulations containing PF11-elaborating herbal products can be applied to the management of opioid withdrawal, the clinical evidence support- ing their use is mixed. For example, WeiniCom is a herbal product mixture that contains Corydalis and Panax quinquefolium; some formulations that are sold online appear also to contain kra- tom (Mitragynia spp.).[67] A double-blind, clin- ical trial compared WeiniCom (also called Xian Xu Qudu Jiaonang) treatment with buprenor-

phine in 42 heroin addicts entering treatment.[68]

WeiniCom not only relieved opioid cravings more rapidly than buprenorphine, it also treated sub- jective measures of withdrawal symptoms such as abdominal pain, diarrhoea, rhinorrhoea, myalgias and piloerection.[68] Adverse effects from WeiniCom were not reported.[68] The beneficial effects from WeiniCom could have been due to kratom be- cause (i) kratom appears to treat opioid with- drawal; (ii) some WeiniCom formulations contain kratom; and (iii) the exact composition of Chinese herbal remedies is often poorly defined.

In addition, a randomized, double-blind, pla- cebo-controlled, multicentre study compared another Chinese herbal mixture called Tai-Kang- Ning with lofexidine in 64 heroin addicts.[69] Im- provement in symptomatology by treatment day 3 was achieved in both groups. Because patients were enrolled up to 36 hours after last heroin use, however, and the symptoms of untreated, acute heroin abstinence resolve in approximately 5 days, this Chinese herbal medication may have actually had little impact on withdrawal.

Although the side-effect profile of traditional Chinese remedies is often unreported, the low incidence of adverse effects compared with lo- fexidine suggests that they are safe to use.[62,69,70]

For example, a product known as FYP (Fu Yan Pellet) was tested against lofexidine in a random- ized, double-blind, placebo-controlled, multicen- tre trial in 225 heroin addicts.[70] In this study, treatment with either FYP or lofexidine decreased opioid withdrawal symptoms by day 3 of treat- ment.[70] The incidence of adverse effects from FYP (e.g. dry mouth) was comparable to that of lofexidine (e.g. dry mouth, transient hypotension and bradycardia). Notably, respiratory depres- sion from traditional remedies has not been re- ported in the peer-reviewed literature.

5. Heantos

Heantos, a complex mixture of materials cre- ated by a Vietnamese herbalist, is intended to treat opioid addiction.[71] Despite funding from the United Nations and other sources, this product has not yet been tested in formal clinical trials.[71]

Furthermore, unconfirmed reports of at least six

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deaths associated with heantos therapy have led Vietnamese authorities to proscribe heantos ther- apy.[72,73] Some investigators suspect that the main component of heantos may be kratom.[72]

6. Conclusions

Clinicians hoping to incorporate herbal rem- edies into treatments for opioid withdrawal and addiction will be confronted by a striking lack of data from well constructed clinical trials in- vestigating the efficacy and effectiveness of these substances. Nonetheless, herbal treatments for problematic opioid use offer some advantages over existing pharmaceutical-based interventions. Some, such as kratom, are believed to have less respiratory depression and fewer lethal side effects than methadone therapy; others, such as traditional Chinese remedies, are less expensive and may be more culturally relevant than standard opioid re- placement protocols. To fully incorporate herbal interventions into existing treatment regimens, several lines of evidence should be developed.

First, the pharmacology, pharmacokinetics and toxicology of herbal materials in humans should be described in greater detail. For example, the pharmacological basis of kratom-associated seizure activity should be investigated, as well as the clinical features that place individuals at risk for this outcome. In addition, the impact of ibo- gaine administration on the QT interval and other cardiac effects should be investigated rather than discounted. Second, sufficient rigor should be incorporated into clinical research studies to allow meaningful assessments of outcome. For example, a study design that compares a remedy with an intervention does not allow clinicians to determine if that remedy is more effective than placebo. If a herbal substance has no benefit, then its use carries only risk; using proper study design would ensure that the potential for benefit can be incorporated into decisions related to medication selection. Third, clinicians should develop the social and cultural contexts in which herbal re- medies have utility. For example, methadone- based opioid detoxification in some cultures has been associated with high rates of relapse and treatment failure. Studies that examine the con-

texts in which culturally relevant interventions may be incorporated into evidence-based treat- ment regimens may improve outcomes. Ultimately, herbal therapies for opioid addiction and with- drawal can complement existing treatments, and future studies should explore the relationship between evidence-based pharmacotherapies and traditional remedies.

Acknowledgements

The authors declare no conflicts of interest. Dr Boyer is supported by NIH ARRA (Challenge) grant RC1-028428. No other sources of funding were used to prepare this review.

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Correspondence: Dr Jeanine Ward, Department of Emer- gency Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. E-mail: Jeanine.ward@umassmed.edu

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