This study sought to determine if the GABA agonist, gabapentin, would be effective in treating the previously described pain intolerance of MM patients. Hypothesized to be a latent hyperalgesia secondary to chronic opioid exposure, it was hoped that this pharmacotherapy might normalize the pain responses of opioid dependent patients, and thus provide a tool for improving the treatment of clinical pain in this at-risk population. Albeit a small sample, these data provide support for the efficacy of GPN to do so for both measures of pain threshold and pain tolerance at methadone peak and trough blood levels.
Importantly, the focus of this paper is specifically to compare those subjects who were compliant in taking the study medication and who remained abstinent from illicit drug use over the course of the 5 week study to controls. Although subjects were encouraged to provide drug-free urine samples via an escalating payment schedule, less than half were able to do so completely. It is well-known that many drugs of abuse, including the CNS stimulants, illicit opioids, and marijuana, can acutely decrease pain, while withdrawal from the same can make nociceptive stimuli feel more painful. Although no overt opioid withdrawal symptoms were noted prior to pain testing, it is unclear how uncontrolled concomitant drug use might have influenced pain responses and GPN efficacy. For this reason, the focus was kept only on abstinent and compliant subjects.
Similar to previous work (Compton et al, 2008
; Doverty et al., 2001
), at baseline, subjects tended to be more sensitive to CP stimulation at peak relative to trough methadone plasma levels. It is possible that these non-significant differences reflect a measurable opioid analgesic effect following methadone dosing, enabling subjects to tolerate the ice bath longer. Alternatively, at trough plasma levels, patients may have been experiencing a mild opioid withdrawal hyperalgesia (see Basbaum, 1991; Compton et al., 2003
; Kaplan & Fields, 1991
) prior to methadone dosing, thus subjects appeared more sensitive to the cold-pressor. Regardless, these differences did not carry over to the post–treatment measures, with significant improvements noted at both peak and trough testing, suggesting that methadone effects on pain responses were not substantively involved in the improvements noted with GPN therapy.
These data are the first to demonstrate that a GABA agonist effectively treats putative opioid-induced hyperalgesia in a clinical sample of methadone patients. Not unlike the considerable effect of GPN on chronic neuropathic pain (Mellegers et al., 2001
; Wiffin et al., 2009
), the general inhibitory effect of GPN on neuronal transmission is evident in central pain systems which have been unregulated secondary to opioid exposure. Singler and colleagues (2007)
observation that the GABA agonist, propofol, mitigates remifentanil-induced hyperalgesia in normal human subjects further supports gabaminergic approaches for the treatment of OIH. Further, these data are also among the first published to demonstrate the effectiveness of GPN to treat OIH in a human model of opioid exposure. Van Elstraete and colleagues (2008)
recently demonstrated that both intrathecal and intraperitoneal GPN administration dose-dependently prevents the hyperalgesia induced by repeated fentanyl administration in uninjured rats; the current findings translate these preclinical observations to a clinical population of humans who receive opioid therapy in the absence of injury or pain.
Pharmacotherapies with activity at non-GABA sites have also been suggested as treatment for OIH. Probably best studied is the relatively weak NMDA-antagonist dextromethorphan, although evidence for its efficacy to offset OIH in clinical samples with pain has been mixed (Compton et al., 2008
; Dudgeon et al., 2007
; Galer et al., 2005
; Haugan et al., 2008
; Heiskanen et al., 2002
; Helmy and Bali, 2001
; Weinbroum et al., 2001
). Other potential agents include CCK antagonists to block descending pain facilitory processes (Gardell et al., 2002
; Vanderah et al., 2001
), and the α2-receptor agonists which attenuated OIH in a small sample of healthy human subjects (Koppert et al., 2003
). Of increasing interest in the literature is the use of low-dose opioid antagonists in conjunction with opioid agonists to counteract the development of OIH (Cepeda et al. 2004
; Chindalore et al., 2005
; and Terner, 2006; Wang et al., 2005
; Webster, 2007
; Webster et al., 2006
), and the use of glial antagonists (i.e., ibudilast) to mitigate the neuroimmune activation associated with opioid administration (Hutchinson et al., 2007
; Watkins et al., 2007
Absolute improvements in cold-pressor responses to GPN were small (2 – 3 seconds), calling into question the clinical significance of these findings. Relative to the short pain threshold and tolerance responses noted at baseline (approx. 7 – 21 seconds), a 3-second change represents a 14% to 43% increase in cold-pressor immersion, thus is clearly significant in this context. Yet, the extrapolation of magnitude of analgesic responses from experimental pain to the clinical pain experience remains an ongoing issue in pain research, (Arendt-Nielsen et al., 2007
; Petersen-Felix and Arendt-Nielsen, 2002
), and one which may never fully be resolved. To the authors’ knowledge there is not a clear cut method for determining the clinical equivalence of changes in cold-pressor pain responses. To provide perspective, CP pain threshold improvement in normal healthy controls to an analgesic dose of morphine (10mg PO) is 5 seconds (Jones et al., 1988
), while improvements in CP tolerance to a 0.5mg/kg dose of morphine PO averaged 10 seconds (Cleeland et al., 1996
; Grach et al., 2004
), thus lengthy changes in cold-pressor pain responses are not associated with clinically potent analgesics.
Several limitations are evident in this work. Firstly, baseline hyperalgesia was not established in this group of subjects, although their average CP pain threshold and tolerance times were consistent with those reported in previous work on this population (Athanasos et al., 2006
; Compton, 1994
; Compton et al., 2000
; Doverty et al., 2001
). Although these data support changes in CP pain threshold and tolerance on GPN, conclusions about changes to OIH specifically must be drawn cautiously. Also, the trial lasted for five weeks, and then subjects were titrated off study mediation; future studies should evaluate the longer-term effects of GPN therapy in this population. Finally, these findings can only be generalized to those MM who are able to abstain from illicit drug use over an extended period of time. In that complete and ongoing drug abstinence is a relatively uncommon outcome of methadone treatment (Johansson et al., 2007
; Maremmani et al., 2007
), the clinical utility of GPN may be limited.
In conclusion, these data support that ongoing GABA agonist therapy, as provided by GPN and under the dosing and clinical conditions evaluated, reduces or mitigates OIH in MM patients. Although the analyzable sample size was small, impressive is the large effect of GPN on CP pain responses in this sample (Cohen’s d
= 1.01 [threshold peak methadone]; 1.73 [threshold trough methadone]; 1.11 [tolerance peak methadone]; 0.30 [tolerance trough methadone]). Like the hyperalgesia of neuropathic pain, OIH appears to respond to GABA-agonist therapy. Gabapentin therapy, in clinically tolerated doses, significantly improved cold-pressor pain responses in methadone patients. These findings suggest that gabapentin might be a useful adjuvant for the significant number of methadone patients who also have chronic pain (Clark et al., 2008
; Rosenblum et al., 2003
; Sheu et al., 2009).