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American Pain Society
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Richard H. Gracely, PhD, Department Editor
Jeffrey S. Mogil, PhD
Clinicians and scientists detest variability. For clinicians, the discovery that even the latest, greatest analgesic does not help some of their patients is puzzling and disappointing. A patient who does not respond to acetaminophen, for example, may be switched to diclofenac and then to ibuprofen in an attempt to achieve satisfactory results. Such idiosyncratic treatment is the norm in the clinic but remains unaccounted for by science. Scientists generally view individual differences in baseline responses to pain and in analgesic responses to an intervention under study as problems to deal with statistically. The most important experimental statistic is the group mean; intragroup variation serves only to obscure differences between the means. Such statistical manipulation makes it possible to assess the effectiveness of an analgesic on the “universal” rat: one with an average sensitivity to pain and an average responsivity to the analgesic being studied.
The larger aim of this research, however, is to advance the argument that, barring the development of a truly novel class of analgesics with greater effectiveness and side-effect profiles superior to willow bark (i.e., nonsteroidal anti-inflammatory drugs, [NSAIDs]) and poppy juice (i.e., opioids), advances in pain management will be attributable mainly to a greater understanding of variability regarding sensitivity to pain, pain pathologies, and analgesic therapies. Such knowledge would make idiosyncratic, patient-centered pain management possible.
Predictions regarding likely future pain levels, analgesic sensitivity, and side-effect sensitivity, based on genetic information collected by venipuncture or buccal swab and environmental information collected by questionnaire or interview, could inform treatment. For some patients, clinicians could make aggressive moves up the World Health Organization analgesic ladder to prevent unnecessary pain. For other patients, cautious dosing could limit side effects without compromising pain relief.
One example of this concept is, in principle, available today. It is well known that the neuronal cytochrome P450IID6 (sparteine/ debrisoquin oxygenase, encoded by the CYP2D6 gene), is absent in approximately 7% to 10% of Caucasians (Meyer, 1994). This rather common genetic polymorphism renders such individuals, called “poor metabolizers,” unable to biotransform codeine into morphine. Because codeine is thought to exert its central analgesic effects as morphine, poor metabolizers receive no therapeutic benefit from codeine administration, although they are subjected to many of the drug’s liabilities. The inherited genetic form (i.e., allele) of CYP2D6 on human chromosome 22 is easily typed, and such typing almost certainly will become faster and less costly in the near future. Before prescribing codeine for a patient, it would seem prudent to determine whether one is giving the patient an efficacious opioid or simply a constipating agent.
Individual differences in susceptibility to pain and analgesia are so taken for granted that few rigorous studies have bothered to document them. Libman’s study (1934) was probably the seminal demonstration of the existence of responders and nonresponders to pain. He reported that pressure applied to the mastoid bone and directed toward the styloid process produced marked pain in 60% to 70% of his patients, whereas the remaining 30% to 40% experienced little or no pain from the same stimulus. Such dichotomous responses have been observed more recently by Chen, Dworkin, and Haug (1989), who used the cold-pressor test: one group could tolerate the stimulus for the full 180-second duration of the test, whereas a second group could tolerate the stimulus only for approximately 50 seconds. Superimposed upon individual differences in pain sensitivity is variability associated with the susceptibility to various kinds of painful pathologies (e.g., back pain, arthritis, phantom-limb pain). Finally, responses to opioids, NSAIDs, and placebos also have been shown to exhibit significant variability (Mogil, 1999).
Three points should be emphasized regarding these individual differences. First, sources extrinsic to the pain-perceiving organism are responsible for much of the variability. For instance, the existence of circadian rhythms of pain and analgesic sensitivity has been well documented (Folkard, 1976). Second, even within organisms, a substantial amount of variation is attributable to nongenetic factors such as past pain experience, age, diet, demographic status, and culture. Some of the variance probably can be explained by factors influenced by and interacting with genetics (e.g., sex, hormonal status, personality, coping styles, cognition, stress), butnot necessarily by the so-called “pain genes.” Some of the variance can be explained by genotype (i.e., inherited allelic forms of pain-relevant genes). Finally, it should be noted that although single-gene pain disorders exist (e.g., congenital insensitivity to pain, familial hemiplegic migraine), it is likely that the normal range of human variation in pain-related traits is attributable to the concerted action of multiple genes interacting with each other and the environment. The polygenic nature of pain represents a major limitation of the transgenic “knockout” mutants currently popular in pain research, in which the effects of the absence of single genes are studied in isolation. Thus, although we presently can identify any number of pain-relevant genes (indeed, the sequence and location of most genes coding for proven pain-relevant proteins are known), we understand much less about which of these genes contributes to individual differences in susceptibility to pain and analgesia.
Although the impending completion of the Human Genome Project will facilitate studies in humans, the literature regarding the genetics of nonpathological pain and analgesia is derived almost entirely from rodent studies. The mouse in particular is a useful model species, largely because there are more than 30 major inbred strains in which each mouse is a clone of every other. We recently published the first systematic survey of the nociceptive sensitivity of a large number of inbred strains of mice on multiple nociceptive assays of this species (Mogil et al., 1999a; Mogil et al., 1999b). Impressive strain differences, corresponding to rough heritability estimates (i.e., the proportion of variance accounted for by inherited genes) of 28% to 76%, depending on the measure, were noted in every assay. A particularly interesting finding from this study concerns the genetic correlation of sensitivity among nociceptive assays. For instance, if a particular strain of mouse is sensitive to the hot plate, what can be predicted regarding its sensitivity to formalin? We found that the 12 measures of nociception we considered fell into three clusters: thermal (hot plate, tail withdrawal, Hargreaves’ test, and, surprisingly, autotomy), chemical (acetic-acid writhing, magnesium-sulfate writhing, and early- and late-phase formalin test), and a broad cluster, including the mechanical von Frey test and three measures of inflammatory and neuropathic hyperalgesia. Another interesting genetic correlation in rodents occurs between initial nociceptive sensitivity and subsequent morphine antinociception (Mogil, 1999). Thus, mice can be “doubly lucky” or “doubly unlucky”: those that are resistant to nociception are sensitive to its inhibition by opioids and vice versa.
To date, only a small number of pain-related traits in mice have ever been subjected to state-of-the-art genetic analyses, such as linkage mapping and subsequent gene identification by positional cloning and/or candidate gene techniques (Lander & Schork, 1994). The inheritance of a pain trait can be followed in a large cohort of mice bred from sensitive and resistant strains and correlated with the inheritance of polymorphic DNA markers (i.e., “microsatellites”) of known location. This technique can localize the relevant genes to broad chromosomal segments. Relevant genes must then be identified from among thousands of neighbor genes. This can be accomplished either through successive rounds of increasingly precise mapping followed by DNA sequencing (positional cloning) or by considering what known genes have already been located in the same chromosomal region (i.e., candidate genes). As greater numbers of murine genes are elucidated by the crucial but largely unheralded Mouse Genome Project, the latter, simpler, approach will become increasingly tenable.
We have enjoyed some success in such efforts to date. Two chromosomal regions statistically associated with variability in morphine analgesia—one on proximal mouse chromosome 10 and another on chromosome 9 (Belknap et al., 1995; Hain, Belknap, Hen, & Mogil, in press)—have been identified. The former contains the Oprm gene, which encodes the mouse m-opioid receptor; the latter contains the Htr1b gene, which encodes the serotonin-1B-receptor subtype. Mapping studies of baseline thermal nociceptive sensitivity to the hot plate and to nonopioid stress-induced analgesia (SIA) have uncovered the existence of sex-specific gene effects. A region of chromosome 4 was found to be associated with hot-plate latency in male, but not female mice (Mogil et al., 1997a); the male-specific gene in question may be Oprd1, which encodes the mouse d2-opioid-receptor subtype. The distal region of mouse chromosome 8 contains a gene responsible for the majority of the genetic variability in endogenous SIA in female mice that have been forced to swim; this unidentified gene is wholly irrelevant to this trait in males (Mogil et al., 1997b).
Although the relevance of tentative gene identification in mice to human variability is unknown, the locations of human analogues of these genes can be predicted by the principle of syntenic conservation (Nadeau & Reiner, 1989). We encourage interested investigators to search for polymorphisms in these genes in humans—an effort that already has begun with the human Oprm gene (Bond et al., 1998).
Belknap, J.K., Mogil, J.S., Helms, M.L., Richards, S.P., O’Toole, L.A., Bergeson, S.E., & Buck, K.J. (1995). Localization to proximal chromosome 10 of a locus influencing morphine-induced analgesia in crosses derived from C57BL/6 and DBA/2 mouse strains. Life Sciences, 57, PL117-PL124
Bond, C., LaForge, K.S., Tian, M., Melia, D., Zhang, S., Borg, L., Gong, J., Schluger, J., Strong, J.A., Leal, S.M., Tischfield, J.A., Kreek, M.J., & Yu, L. (1998). Single-nucleotide polymorphism in the human mu opioid receptor gene alters b-endorphin binding and activity: Possible implications for opiate addiction. Proceedings of the National Academy of Sciences, USA, 95, 9608-9613.
Chen, A.C.N., Dworkin, S.F., & Haug, J. (1989). Human pain responsivity in a tonic pain model: Psychological determinants. Pain, 37, 143-160.
Folkard, S. (1976). Diurnal variation and individual differences in the perception of intractable pain. Journal of Psychosomatic Research, 20, 289-301.
Hain, H.S., Belknap, J.K., Hen, R., & Mogil, J.S. (in press). Pharmacogenetic evidence for the involvement of serotonin-1B (5-HT1B) receptors in the mediation of morphine analgesic sensitivity. Journal of Pharmacology and Experimental Therapeutics.
Lander, E.S., & Schork, N.J. (1994). Genetic dissection of complex traits. Science, 265, 2037-2048.
Libman, E. (1934). Observations on individual sensitiveness to pain. Journal of the American Medical Association, 102, 335-341.
Meyer, U.A. (1994). The molecular basis of genetic polymorphisms of drug metabolism. Journal of Pharmacy and Pharmacology, 46, 409-415.
Mogil, J.S. (1999). The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proceedings of the National Academy of Sciences, USA, 96, 7744-7751.
Mogil, J.S., Richards, S.P., O’Toole, L.A., Helms, M.L., Mitchell, S.R., & Belknap, J.K. (1997a). Genetic sensitivity to hot-plate nociception in DBA/2J and C57BL/6J inbred mouse strains: Possible sex-specific mediation by d2-opioid receptors. Pain, 70, 267-277.
Mogil, J.S., Richards, S.P., O’Toole, L.A., Helms, M.L., Mitchell, S.R., Kest, B., & Belknap, J.K. (1997b). Identification of a sex-specific quantitative trait locus mediating nonopioid stress-induced analgesia in female mice. Journal of Neuroscience, 17, 7995-8002.
Mogil, J.S., Wilson, S.G., Bon, K., Lee, S.E., Chung, K., Raber, P., Pieper, J.O., Hain, H.S., Belknap, J.K., Hubert, L., Elmer, G.I., Chung, J.M., & Devor, M. (1999a). Heritability of nociception. I. Responses of eleven inbred mouse strains on twelve measures of nociception. Pain, 80, 67-82.
Mogil, J.S., Wilson, S.G., Bon, K., Lee, S.E., Chung, K., Raber, P., Pieper, J.O., Hain, H.S., Belknap, J.K., Hubert, L., Elmer, G.I., Chung, J.M., & Devor, M. (1999b). Heritability of nociception. II. “Types” of nociception revealed by genetic correlation analysis. Pain, 80, 83-93.
Nadeau, J., & Reiner, A.H. (1989). Linkage and synteny homologies in mouse and man. In M.F. Lyon & A.G. Searle (Eds.), Genetic variants and strains of the laboratory mouse (pp. 506-536). Oxford, England: Oxford University Press.
Jeffrey S. Mogil is an assistant professor in the department of psychology and a faculty member of the neuroscience program at the University of Illinois at Urbana-Champaign.
