Tramadol [(±)-trans-2-(dimethylaminomethyl)-1-(m-methoxyphenyl)-cyclohexanol hydrochloride] was introduced as a non-scheduled drug on the market in the US in 1995 for treatment of moderate to moderately severe pain. It had been available in Germany since 1977. As a centrally acting analgesic, tramadol is atypical because it produces analgesia through both mu opioid and monoamine actions (Bamigbade, Davidson, Langford, & Stamford, 1997
; Driessen & Reimann, 1992
; Driessen, Reimann, & Giertz, 1993
; Raffa et al., 1992
). The pharmacology of tramadol is further complicated by the fact that it is administered as a racemic mixture with two active enantiomers (Raffa et al., 1993
), each of which is biotransformed to an active metabolite: (+)-O-desmethyltramadol or (−)-O-desmethyltramadol (Valle, Garrido, Pavon, Calvo, & Troconiz, 2000
). These metabolites are believed to be responsible for most of tramadol’s mu-agonist properties (Gillen, Haurand, Kobelt, & Wnendt, 2000
Results of Animal Studies
Only a few self-administration studies with tramadol have been published. Yanagita (1978)
conducted three tramadol self-administration experiments in rhesus monkeys. In one study, four monkeys were trained to self-administer lefetamine, an amphetamine with opioid-agonist activity. After lefetamine self-administration had stabilized at approximately 100 injections per 4-hr session (0.1 mg/kg/injection), saline was substituted until responding extinguished. Lefetamine and saline availability were switched repeatedly until reinstatement of responding and extinction occurred reliably within 24 hours. When tramadol (0.25 mg/kg/injection) was substituted for lefetamine, the number of injections fell to 41.0% (range 14.7–69.6%; SD 22.5%) of those taken when lefetamine was available, not significantly higher than the proportion taken when saline was available (14.1; range 7.6–23.1; SD 6.5%). In a second study, four rhesus monkeys, two naïve and two self-administration experienced, were given unrestricted access to tramadol. In all four monkeys, rates of operant responding for drug increased above saline levels when the dose/injection of tramadol was increased to 1.0 mg/kg. Two of the monkeys also participated in a third study with tramadol 1.0 mg/kg injection available on a progressive-ratio schedule. The maximum response ratios that the monkeys completed for injections were 64:1 and 32:1; these values were less than the 128:1 ratio expected for other known analgesics such as morphine. The author concluded that tramadol had reinforcing effects but that these effects were less than those of pentazocine (Yanagita, 1978
More recently, however, tramadol was shown to produce conditioned place preference in rats (Sprague et al., 2002
; Tzschentke, Bruckmann, & Friderichs, 2002
). The effects of tramadol on place preference were similar in magnitude to those of morphine, which served as a positive control in each study. Preference for the tramadol-associated compartment of the conditioning box produced by 10 mg/kg (i.p.) was prevented by pretreatment with naloxone 0.215 mg/kg (s.c.) (Tzschentke et al., 2002
In the drug-discrimination paradigm, tramadol was tested in rats trained to discriminate 4.0 mg/kg morphine from saline and in rats trained to discriminate 0.5 mg/kg methamphetamine from saline (Ren & Zheng, 2000
). Tramadol fully substituted for morphine, with approximately 96% of responses on the morphine-appropriate lever when tramadol doses reached or exceeded 32 mg/kg. This effect was completely blocked by concomitant administration of naltrexone. Tramadol did not substitute for methamphetamine at any dose tested (3.2 – 56 mg/kg). Tramadol also failed in rats to substitute for the flupirtine, a novel analgesic with probable alpha-2 adrenergic actions, or for anpirtoline, a drug with serotonergic actions (Swedberg, Shannon, Nickel, & Goldberg, 1988
The capacity of tramadol to produce physical dependence has been tested in mice, rats, and rhesus monkeys. The results of these studies have been mixed. Miranda & Pinardi (1998)
administered tramadol (39.1or 100 mg/kg; sc) three times daily for five days to mice and then tested them for tolerance in an experimental pain model (the acetic acid writhing test) and for physical dependence by injection with naloxone (1 mg/kg; i.p.). There was no evidence of tolerance to the antinociceptive response to the ED50 dose (7.82 mg/kg) of tramadol, and there were few or no signs of withdrawal after administration of naloxone at either dose of tramadol. In contrast, a control group that received an identical regimen of morphine (1.05 or 100 mg/kg) injections showed significant tolerance to the morphine ED50 dose (0.21 mg/kg) and showed opiate-withdrawal signs on administration of naloxone. Almost no cross-tolerance was demonstrated: the antinociceptive response to tramadol was unchanged in the morphine-treated group, and there was only a trend for decreased response to morphine in the tramadol-treated group. Thus, tramadol produced neither tolerance nor physical dependence in mice. Similarly, Murano et al. (1978)
evaluated tolerance and physical dependence in rats treated with up to 160 mg/kg/day in four divided s.c. injections. Tolerance to tramadol’s antinociceptive effects was observed, but there was no evidence of physical dependence as indicated by weight loss following abrupt discontinuation of tramadol administration or following administration of levallorphan. However, some evidence of physical dependence was detected in rats receiving tramadol orally (50 mg/kg/d) and subjected to 24-hr withdrawal with or without injection of naloxone (Nickel & Aledter, 1987
). Similarly, there was some evidence of withdrawal in eight rhesus monkeys receiving tramadol four times a day (32 to 96 mg/kg/day; s.c.) for 59 days: although few or no withdrawal signs were seen when naloxone (1.0 mg/kg; s.c.) was administered on four occasions during the administration period, withdrawal signs did emerge in the five days after tramadol was discontinued. These signs were graded as only mild (or, after the highest dose regimen, intermediate), not progressing to such severe signs as vomiting or diarrhea (Yanagita, 1978
). In a concurrently run experiment, four rhesus monkeys self-administering tramadol for four to six weeks and administered naloxone (1.0 mg/kg; s.c.) at weeks 2 and 4 showed only mild-to-moderate withdrawal signs. The author concluded that the physical-dependence potential of tramadol is lower than that of pentazocine (Yanagita, 1978
No antagonist activity has been demonstrated for tramadol in laboratory animals. Tramadol had only additive effects in an analgesic assay when combined with low doses of morphine and did not precipitate withdrawal jumping in morphine-dependent mice (Friderichs, Felgenhauer, Jongschaap, & Osterloh, 1978
In summary, results of animal studies suggested that tramadol is an atypical opioid analgesic. It has some abuse potential, but, based on the self-administration studies in monkeys, less than that of prototypic opioids such as morphine. The evidence for physical-dependence capacity is mixed; withdrawal was not detected in mice, withdrawal was not detected consistently in rats, and only mild-to-moderate withdrawal was detected in rhesus monkeys.
Results of Human studies
There are no published human studies on self-administration or discrimination of tramadol; however, it has been investigated in a series of single-dose subjective-effects studies by several routes of administration.
The first abuse-liability study assessed the subjective, behavioral, and miotic effects of intramuscularly administered tramadol (75, 150 and 300 mg) compared to those of morphine (15 and 30 mg; i.m.), and placebo in 12 non-dependent opiate abusers. The results suggested that tramadol had a low abuse potential, at least when administered by the intramuscular route (Preston, Jasinski, & Testa, 1991
). On subjective measures of opiate-like and positive mood effects, tramadol 75 and 150 mg were not different from placebo. Tramadol 300 mg was identified as an opiate but did not produce other morphine-like effects. Consistent with its not being a typical opioid and having inhibitory activity at catecholamine-reuptake sites, tramadol initially induced mydriasis (an increase in pupil diameter). In contrast, morphine induced miosis (a decrease in pupil diameter), as well as typical opioid-agonist-like subjective effects and identification as an opiate. Tramadol was expected to be one-tenth as potent as morphine based on its analgesic effects in other studies (Gutstein & Akil, 2001
); however, in terms of opiate-like subjective effects, it was estimated to be only one twentieth as potent as those of morphine. Thus, the results showed a dissociation between tramadol’s potency as an analgesic and as an inducer of opioid-like subjective effects, consistent with its having a low potential for abuse when administered intramuscularly.
Abuse of prescription medications is more likely to occur by the oral route or by intravenous injection of crushed, dissolved oral formulations. Therefore, our laboratory has conducted evaluations of intravenously and orally administered tramadol in experienced opioid abusers. These studies have been reported only in abstract form (Jasinski, Preston, Sullivan, & Testa, 1993
) or as a conference presentation (Jasinski, Sullivan, & Testa, 1994
). The studies were approved by the appropriate Institutional Review Board for human research, and participants gave informed consent and were paid for their participation.
In an initial intravenous dose-ranging study, tramadol (700 mg; i.v.) administered over 1 min produced a seizure, as did a lower dose (300 mg; i.v.) delivered over 2.5 min. Thus, toxicity is likely to limit abuse of high doses of IV tramadol. At a lower dose (200 mg; i.v) administered over 5 min, no seizures occurred.
In a follow-up crossover study of intravenous tramadol, 10 experienced opioid abusers were tested with placebo, morphine (10 and 20 mg; i.v.), and tramadol (100 and 200 mg; i.v.) administered over 5 minutes according to two 5×5 balanced Latin squares under double-blind conditions. Both tramadol and morphine significantly increased ratings of “feel drug effect” compared to placebo. Morphine 10 and 20 mg significantly increased ratings of “liking,” and morphine 20 mg increased ratings on the ARCI MBG scale (). In contrast, neither dose of tramadol increased ratings on the liking or MBG scales () or on any other subjective measure of opiate-like effects.
Figure 1 Mean area under the curve scores produced by intravenously administered tramadol, morphine, and saline placebo on “Liking” and MBG scale scores in 10 experienced opioid abusers. Brackets indicate one half of Fisher’s Least Significant (more ...)
A very different pattern of effects was produced when tramadol was administered orally. Tramadol (175, 350, and 700 mg; p.o.) was compared to placebo and oxycodone (20 and 40 mg; p.o.) in 12 experienced opioid abusers in two 6×6 balanced Latin squares under double-blind conditions. Tramadol and oxycodone both increased ratings on the MBG scale of the ARCI and were identified by participants as opiate-like on a questionnaire that listed various drug classes (data not shown). Tramadol and oxycodone also decreased pupil diameter and increased ratings on the “feel drug” and “liking” scales (). However, the maximum responses to tramadol occurred much later than the maximum responses to oxycodone (, right panels). These findings are consistent with the observation that tramadol’s mu-agonist properties require its biotransformation to an active metabolite.
Figure 2 Maximum effects (left panel) and time to maximum effect (right panel) of orally administered tramadol, oxycodone, and placebo on pupil diameter, and “Feel drug,” and “Liking” scores in 12 experienced opioid abusers. Brackets (more ...)
The physical-dependence capacity of tramadol has not been evaluated in human laboratory studies as it has for buprenorphine and nalbuphine (Jasinski & Mansky, 1972
; Jasinski, Pevnick, & Griffith, 1978
). However, development of dependence was evaluated during a clinical trial of tramadol for treatment of severe pain (Richter, Barth, Flohe, & Giertz, 1985
). Patients were treated orally with tramadol capsules up to a maximum of 400 mg/day for three weeks (mean dose approximately 250 mg/day); there was no evidence that tolerance developed to the analgesic effects. At the end of the three-week treatment, patients were randomized to receive naloxone (1.6 mg; i.m.) or placebo under double-blind conditions three hours after the last tramadol ingestion. Three of 54 participants showed marginal or slight elevations in opiate-withdrawal scores following naloxone, while 1 of 55 participants showed a marginal elevation in opiate-withdrawal scores following placebo. This difference was not statistically significant. Thus, under conditions of intermediate duration of tramadol administration within the recommended oral dose range, there was no strong evidence for development of physical dependence.
The opioid antagonism of tramadol was assessed in 6 male opioid-dependent volunteers who had been maintained on methadone (30 mg/day; p.o.) for at 10 days prior to the study (Cami, Lamas, & Farre, 1994
). The subjective, behavioral, and physiological effects of tramadol (100 and 300 mg; i.m.) were not significantly different from those of placebo. Tramadol neither produced morphine-like effects nor precipitated a withdrawal syndrome. Thus, there was no evidence that tramadol has antagonist activity.
In summary, opiate-like effects were produced by oral but not parenteral administration of tramadol. There was minimal evidence for physical dependence and no evidence for opioid antagonism. Unlike other opioids, tramadol’s abuse-potential indices appeared low relative to its analgesic potency, at least by parenteral routes.
Tramadol was approved by the FDA in 1998 for the management of moderate to moderately severe pain under the brand name Ultram without being scheduled under the Controlled Substances Act. The FDA, however, required that the sponsoring company conduct postmarketing surveillance of abuse and diversion. The tramadol surveillance program included: spontaneous reports to the manufacturer; adverse-event data from the FDA’s MedWatch; a key-informant network of treatment researchers who completed quarterly questionnaires; and monitoring of tramadol use in a population of impaired professionals (Cicero et al., 1999
; Knisely, Campbell, Dawson, & Schnoll, 2002
; Woody et al., 2003
). This combination of elements greatly increased the program’s sensitivity relative to that of MedWatch alone. MedWatch is a program maintained by the FDA to collect adverse-event reports on marketed medications from health-care providers, drug companies, and individual consumers, and to provide safety information for health-care professionals and the public (Corrigan, 2002
; Woody et al., 2003
); it does not specifically target abuse or dependence as adverse events, nor does it target specific medications. In contrast, the tramadol key-informant-network program solicited reports of tramadol abuse at three-month intervals from drug-abuse experts (including researchers, clinicians, treatment counselors, and methadone-program directors) and conducted Internet searches for information on tramadol abuse (Cicero et al., 1999
). The impaired-professionals surveillance recruited participants from monitoring programs in four states (Florida, Illinois, Pennsylvania, and Washington) (Knisely et al., 2002
). Urine specimens collected as part of the monitoring programs were tested for tramadol. Participants were asked to report all drug use at each urine collection but were not aware that tramadol was the drug of interest. Findings from all of these programs are summarized in the .
Summary of abuse and dependence liability studies of tramadol
Reports from MedWatch and the key-informant program showed a low rate of abuse of tramadol, initially rising and then falling during the first three years of its availability in the US (Cicero et al., 1999
). The rate of abuse peaked at two to three cases per month per 100,000 patients exposed during the first two years, then fell at three years to approximately one case per month per 100,000 patients exposed. In contrast, during the same period, the number of patients who were prescribed tramadol increased from 700,000 in the first year to about 900,000 in the third year. Internet searches identified more than 150 mentions over six months of the mood effects of tramadol. Most of the mentions indicated that tramadol did not produce euphorigenic effects, though a small number did report mood alteration or enhancement of the effects of other drugs.
Results from the postmarketing surveillance in impaired health-care professionals showed a similarly low rate of abuse among at-risk individuals (Knisely et al., 2002
). The incidence of tramadol use, including legitimate prescription use, was 69 per 1000 individuals per year in 1601 impaired professionals participating in state monitoring programs between November 1995 and August 1998. Approximately one third (560) were primary opioid abusers. The incidence of tramadol abuse was approximately one tenth of that rate, 6.9 per 1000 individuals per year. Within the entire sample of 1601 individuals, 140 ever used tramadol and 15 met the study’s criteria for abuse/dependence. The authors considered this rate very low, given that the population studied was at high risk for relapse.
The MedWatch reports and postmarketing surveillance were also used to investigate whether tramadol produces physical dependence and a withdrawal syndrome (Senay et al., 2003
; Woody et al., 2003
). During the first three years of surveillance, 1248 adverse events were reviewed (Senay et al., 2003
). Approximately one third (N=422) were rated as withdrawal, with most (N=367) indicating typical opioid withdrawal-like signs and symptoms, but with a small proportion (N=55) identified as atypical (not opioid withdrawal-like). The typical opioid withdrawal signs and symptoms included abdominal cramps, anxiety, bone pain, depression, diarrhea, goose flesh, insomnia, lacrimation, nausea, restlessness, rhinorrhea, and sweating. The atypical-withdrawal reports fell into four categories: severe anxiety and panic attacks, unusual CNS symptoms, unusual sensory phenomena, and hallucinations. CNS symptoms included confusion, depersonalization, derealization, and paranoia. Sensory phenomena reported were numbness, tingling, paresthesia, and tinnitus. The signs and symptoms of atypical withdrawal are similar to the discontinuation syndrome reported for selective serotonin reuptake inhibitors (SSRIs) (Bogetto, Bellino, Revello, & Patria, 2002
; Rosenbaum, Fava, Hoog, Ascroft, & Krebs, 1998
Clinical experiences with abuse and dependence can also be gleaned from published case reports. The case reports on tramadol have generally been consistent with the results of the formal postmarketing studies, describing incidents of abuse with and without prior history of other substance abuse (Ehrenreich & Poser, 1993
; Lange-Asschenfeldt, Weigmann, Hiemke, & Mann, 2002
; Reeves & Liberto, 2001
), or describing physical dependence with a discontinuation syndrome in both abusers and in non-abusing patients (Barsotti, Mycyk, & Reyes, 2003
; Freye & Levy, 2000
; Leo, Narendran, & DeGuiseppe, 2000
; Thomas & Suresh, 2000
; Yates, Nguyen, & Warnock, 2001
Comparison between laboratory-animal data and human data
The summarizes findings from laboratory animals and humans, and contrasts those findings with epidemiological findings.
The results of laboratory tests have generally been consistent across primate species: in rhesus monkeys, tramadol is self-administered only to a modest degree, and in humans, tramadol elicits only modestly positive subjective effects. Each of these findings seems to have been appropriately predictive of the clinical and epidemiological experience with tramadol; postmarking data, case reports, and Internet mentions all suggest that tramadol is rarely perceived as a highly desirable euphoriant.
In light of this, data from rat models of abuse potential seem to represent false positives. In rats, tramadol produces fairly robust conditioned place preference and fully substitutes for the morphine discriminative stimulus. There are at least two possible explanations for this cross-species discrepancy. First, the biotransformation of tramadol to its main active metabolites is known to be much more rapid and complete in rats than in humans; 72 hours after administration of tramadol, humans excrete 25–32% of the dose unmetabolized, while rats excrete only 1% unmetabolized (Lintz, Erlacin, Frankus, & Uragg, 1981
). The metabolites are believed to be responsible for most of tramadol’s mu-agonist properties (Gillen et al., 2000
), so more rapid and complete biotransformation is consistent with greater abuse potential. Second, direct cross-species comparison is hampered by the use of different paradigms in difference species. The monkey and human studies used self-administration and subjective-effects measures, respectively; the rat studies used conditioned place preference and drug discrimination. Therefore, the apparently superior predictive value of the monkey and human data cannot be decisively attributed to species differences. An organized, integrated program of cross-species assessment, like the one formerly in place, would be desirable.
Data on tramadol’s capacity to produce physical dependence appear more consistent across species, with the exception of one negative finding in mice. Rats and rhesus monkeys showed evidence of mild withdrawal symptoms; the occurrence of such symptoms in humans has been borne out by postmarketing surveillance and case reports, as has the symptoms’ relative mildness. Still, there are gaps in our knowledge. It has not been directly demonstrated that the withdrawal syndrome seen in humans is mediated primarily through opioid receptors; in fact, as discussed above, some of the withdrawal symptoms seen in humans resemble those seen with discontinuation of SSRIs. These so-called “atypical” withdrawal symptoms have not been reported in other species, but this may be due to their not having been systematically assessed. Again, these gaps in our knowledge suggest benefits that would accrue from an organized, integrated program of cross-species assessment.
As summarized in the , the tramadol experience in the US seems to represent a successful case of premarketing assessment for abuse and dependence potential that led to appropriate scheduling of a medication. While data from rodents suggests that some restrictions on availability would be necessary, data from primates and humans suggested that these restrictions could be minimal; postmarketing data suggest that the decision not to schedule tramadol was correct.
Nevertheless, the tramadol data also point to areas where premarketing screening could be improved. First, the use of different paradigms in different species precludes direct comparison of interspecies data. Most of the paradigms reviewed in this article can be used in rodents, monkeys, and humans; investigators should make more concerted efforts to see that this is done. Second, assuming for the moment that differences in paradigms can be overlooked, the pattern of premarketing results with tramadol suggest that rodent studies are useful but not sufficient for predicting abuse and dependence potential. Although it could be argued that tramadol is a special case because of its complex pharmacology (in particular, being both a drug and a prodrug), species differences in metabolic pathways and receptor profiles are likely to affect findings with other drugs as well. The current reliance on rodent models, while expedient in terms of drug throughput, increases the likelihood that a useful medication might be abandoned or too highly restricted due to exaggerated indices of abusability (or not sufficiently restricted due to insufficient detection of abusability). Rodent, monkey, and human studies should again be conducted in an integrated manner.