Opioids: A review

Opioids: A Review Eric Chevlen, MD

Address Cancer Care Center, St. Elizabeth Hospital, 1044 Belmont Avenue, Youngstown, OH 44501, USA. E-mail: [email protected] Current Pain and Headache Reports 2003, 7:15–23 Current Science Inc. ISSN 1531–3433 Copyright © 2003 by Current Science Inc.

Recent discoveries in opioid pharmacology help explain the enormous variability in clinical responses to these powerful analgesics. Although there is only one µ opioid receptor gene, splice variants of that gene’s expression result in a panoply of different functioning receptors. Other sources of variable response include polymorphisms in the µ opioid receptor regulatory region, and pharmacokinetic differences because of cytochrome P-450 mono-oxygenase heterogeneity. Analgesic tolerance is likely the key phenomenon limiting the benefit of opioids. A plethora of intracellular pathways affects this. Among them are the Nmethyl-D-aspartate receptor, protein kinase C ␥ activity, nitric oxide synthase, and GM1 ganglioside content of the neuronal membrane. Clinical studies undercut the routine use of meperidine in most settings. Other studies have shown better ways to diminish opioid side effects.

Introduction We are rapidly approaching the 200th anniversary of Sertürner’s isolation of morphine and his discovery that it is the chief active ingredient of opium. This may be seen as the beginning of the modern era in analgesia. Other landmarks include the invention of the hypodermic syringe in 1853 by Alexander Wood, and the discovery in 1973 by Pert and Snyder of “the opiate receptor,” a discovery that would now be described as an opioid receptor [1]. Despite this seemingly long history of drug development, and despite a veritable flood of recent discoveries in the field of opioid analgesia, many fundamental questions remain unanswered, or at least answered incompletely. This review summarizes important discoveries and developments, and points to areas of ongoing research in which further discoveries are expected.

Opioid Receptors Opioids exert their pharmacologic effect by binding to receptors found throughout the body, but especially in the nervous system. The opioid receptors belong to the

superfamily of G-protein coupled receptors, which contain seven transmembrane regions with the amino terminus outside the cell and the carboxy terminus within it [2]. Within the membrane, the opioid receptors form a doughnut-shaped structure, with the binding site in the center [3••]. The opioid receptors interact with heterotrimeric G-proteins, which serve as the transduction system for conveying the binding signal into the cell. In neurons of the pain pathway, these receptors perform a number of critical actions. They stimulate an inwardly rectifying potassium conductance through a pertussis toxin-sensitive G-protein [4]. They inhibit adenylate cyclase, thereby diminishing intracellular synthesis of cyclic adenosine monophosphate AMP). They also inactivate voltagegated Ca++ channels [5]. All of these actions result in a reduction of neurotransmitter release. Initially, three types of opioid receptors were defined— the µ, κ, and δ opioid receptors [6]. Recently, a fourth kind of receptor and its endogenous ligand have been identified. The new opioid receptor was first identified on the basis of cDNA cloning studies. It did not show high affinity for any of the known opioid ligands, so it was called an “orphan” receptor. The human form of this receptor is called ORL1 because it was perceived to be opioid receptor-like. The endogenous ligand for ORL1 is a 17-amino acid peptide that resembles dynorphin, and it has been named orphanin FQ and nociceptin (Noc/OFQ). ORL1 is expressed widely in the nervous system, and it is likely that it and Noc/OFQ participate in a broad range of physiologic and behavioral functions [7]. Noc/OFQ is synthesized by the cleavage of a precursor molecule, prepronociceptin/ orphanin FQ (ppNoc/OFQ). That same precursor molecule also is the source of nocistatin, a recently identified neuropeptide that, although it does not bind to ORL1, antagonizes the action of Noc/OFQ and plays important roles in learning, memory, and the regulation of pain transmission [8]. Most opioid analgesics relieve pain by their action on the µ opioid receptor (MOR). Unlike the expression of δand κ-opioid receptors, MOR expression does not occur in embryonal cells. It requires neural differentiation and probably the activity of neural cell adhesion molecules [9]. The transcription of the MOR gene is controlled by two promoter regions, located a few hundred base pairs away from the start of the amino acid coding region [10•]. Here, a number of transcription factors can up- or down-regulate MOR expression [11]. Methylation of cytosines located on the 5 prime side of guanosine is known to have a profound

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Table 1. Sources of variation in opioid analgesic response MOR splice variants MOR density MOR polymorphisms CYP2D6 activity level Clinical factors (eg, pain intensity, pain duration, tolerance, expectation, social milieu, anxiety) MOR—Mu opioid receptor.

effect on the expression of several eukaryotic genes. This method of regulating gene transcription appears to be active in control of MOR expression in neural cells [12]. The fundamental basis of modern genetics is the recognition that genes are encoded in DNA. However, not all of the base pairs in the gene are expressed in the protein product encoded by the gene. Long stretches of DNA may intrude within the regions that are ultimately transcribed by mRNA and translated into the functional protein. These intruding regions are called introns, and the expressed regions of DNA are called exons. The first cloned MOR, MOR-1, contains four exons. Exon 1 encodes the extracellular component of MOR and some of the transmembrane region. Exons 2 and 3 each encode three additional transmembrane regions, and exon 4 encodes a small region at the tip of the intracellular component of the MOR [3••].

Variation in Opioid Response Only one MOR gene has been identified. However, multiple lines of evidence support the concept of multiple µ opioid receptors. How are these conflicting data reconciled? It is likely that alternative splicing of the gene is a large part of the answer. Within the long µ opioid receptor gene are multiple areas of alternative expression. Similarly, exons may be spliced or truncated at different sites, leading to variability on the structure of the MOR itself. Splice variants of the MOR were discovered soon after the initial description of MOR-1. One variant had a truncated expression of exon 4 [13]. The other substituted a different exon, labeled exon 5, in place of the exon 4 that was expressed in MOR-1 [14]. At least seven different splice variants have been described, and there are others awaiting formal description [15]. These splice variants of the MOR are not merely laboratory phenomena of interest to the cell biologist. It is likely that they play a role in the enormous variability in the human response to different opioids. Obviously, the investigation of variable analgesic response is more easily accomplished in animal models than in humans. One of the most fascinating animal models is the CXBK strain of the mouse. This animal shows virtually no analgesic response to morphine, but it remains sensitive to the analgesic effects of fentanyl, heroin, and the morphine metabolite morphine-6 β-glucuronide and other opioid agonists [16].

Splice variants are not the only cause of genetic variation in the experience of pain (Table 1). Humans differ from one another in MOR densities in the brain [17•]. Polymorphisms of the MOR, in the expressed and regulator regions, have been described in humans [18]. That these polymorphisms will be found to correlate with pain experience or analgesic effect seems likely because ongoing studies already suggest an association between specific point mutations in the MOR and susceptibility to drug addiction [19]. Furthermore, we should not limit our search for causes of variation in analgesic response to the MOR. The cytochrome p450 mono-oxygenase system (CYP) influences the response to a large number of drugs, including several opioid analgesics [20••]. In particular, two of the enzymes of this system, CYP2D6 and CYP3A4, are responsible for a large portion of its overall activity. There is enormous ethnic variation in the expression of these enzymes. For example, 6% of the white population has essentially no activity of the CYP2D6 enzyme. Enzyme activity studies in other ethnic groups show wide variation among the groups [21]. Further compounding the variability in human response to analgesics is that many commonly used drugs, such as selective sertonin reuptake inhibitor antidepressants, neuroleptics, and antihistamines, inhibit the activity of CYP2D6. Perhaps the biggest impact of CYP2D6 is in the use of codeine. Codeine essentially is an inactive prodrug that is converted intracellularly to morphine by the CYP2D6 enzyme [22]. Patients who are deficient in that enzyme or who are taking another drug that inhibits the enzyme’s activity would be unlikely to get much analgesia from it. Tramadol is an atypical analgesic; its actions probably depend on its ability to inhibit norepinephrine reuptake and its ability to act as an agonist at µ opioid receptors. The latter effect results from an active metabolite, O-desmethyl tramadol, whose synthesis is catalyzed by CYP2D6. Patients with low CYP2D6 activity treated with tramadol have a reduced analgesic response to experimental pain compared with subjects whose enzyme activity is normal [23]. However, hydrocodone, although it is metabolized to hydromorphone by CYP2D6, does not lose its analgesic activity with the co-administration of an inhibitor of CYP2D6 [24]. The effect of CYP2D6 on methadone metabolism is even more complex. Methadone inhibits the activity of the enzyme, but is itself metabolized by it. Moreover, the metabolic effect of the enzyme differs for the two stereoisomers of methadone [25,26].

Opioid Tolerance Opioid tolerance is disarmingly easy to define and simple to demonstrate in laboratory animals. In 2001, the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine issued a consensus statement defining tolerance as “a state of adaptation in which exposure to a drug induces

Opioids: A Review • Chevlen

Table 2. Key pathways in opioid tolerance N-methyl-D-aspartate receptor activity Intracellular magnesium concentration Protein kinase C gamma activity Nitric oxide synthase activity Coupling of mu opioid receptor to excitatory G-protein Cyclooxygenase activity in dorsal horn neurons GM1 ganglioside density in neuronal membrane Mu opioid receptor internalization

changes that result in a diminution of one or more of the drug’s effects over time” [27••]. However, elucidating its mechanisms remains an ongoing challenge; the ultimate control of opioid analgesic tolerance is of such importance that it has been called the Holy Grail of pain medicine research [28•]. As if the physical factors involved in opioid tolerance were not challenging enough, there is evidence to show that an animal made tolerant to morphine in one environment will not exhibit tolerance in a different environment [29]. A number of important elements of opioid analgesic tolerance have been identified (Table 2). Each experiment in the field, if taken in isolation, would seem to suggest that its particular mechanism is the key step in tolerance. However, taken together, these experiments remind us of the fable of the six blind men and the elephant, as was famously versified by the American poet John Godfrey Saxe [30]. One of the most important neurotransmitters in the pain pathway is glutamate. Among other sites, it is released at the synapse between the primary nociceptive neuron and the second neuron in the pain pathway in the superficial laminae of the dorsal horn of the spinal cord. Glutamate may bind to two categories of glutamate receptors: metabotropic, whose activation leads to the modulation of cell activity by G-proteins and secondary messenger systems, and ionotropic, whose activation leads to action potentials and transmission of pain information [31]. In the category of ionotropic receptors, there are three subtypes defined by the ligands used to study them in vitro. These are the kainate, ␣-amino-3-hydroxy-5-methyl-4isoxazoleproprionate, and N-methyl-D-aspartate (NMDA) receptors. Of these, the NMDA receptor is an important component of the physiologic machinery of opioid analgesic tolerance. Ongoing noxious stimulus leads to activation of the NMDA receptor, with a consequent influx of calcium ions into the neuron. The influx of calcium ions is a critically important event in the subsequent translocation and activation of protein kinase C (PKC), the increase of nitrous oxide (NO) within the cell, and blunted responsiveness of the µ opioid receptor [32••,33]. Persistent noxious stimuli recruit the NMDA channel, leading to windup and central sensitization, a phenomenon whose behavioral correlate is hyperalgesia [34]. However, it is not only noxious stimuli, or even neuropathic pain that recruits NMDA channel activity. Opioids do it as

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well. For example, animals treated with morphine or fentanyl will exhibit less response to a noxious stimulus. However, blocking that opioid response with naloxone does not return the animals to their baseline responsiveness, but renders them more responsive to the noxious stimulus (ie, hyperalgesic). The opioid-induced hyperalgesia is unmasked by the naloxone treatment. Opioid-induced hyperalgesia may be prevented by the co-administration of an NMDA antagonist, showing the importance of this receptor in the phenomenon [35]. Similarly, mice treated for 6 days with implanted morphine pellets will exhibit thermal hyperalgesia and mechanical allodynia after the pellet is removed. Evidence that this effect depends on the µ opioid receptor is that CXBK mice, which lack the morphine-binding MOR, do not develop morphine-induced hyperalgesia [36•]. Numerous animal studies show that inhibition of the NMDA receptor at a number of its available binding sites can prevent or reverse opioid analgesic tolerance [37•]. This technology is now finding its way into clinical practice. The ability of the NMDA-antagonist ketamine to reverse opioid tolerance has been reported in a small, short-term, randomized, double-blind clinical trial in patients with cancer [38•]. A larger and longer randomized, double-blind clinical trial showed benefit of the NMDA antagonist dextromethorphan in cancer pain and non-malignant pain [39]. Ongoing studies are aimed at bringing NMDA-receptor blockade into clinical practice to enhance analgesia and reduce opioid tolerance [40•]. As previously noted, the influx of ionized calcium into the dorsal horn neuron activates PKC. More precisely, in the dorsal horn neurons, the calcium ions activate the gamma isoform of PKC (PKC ␥), one of at least 12 isoforms of that enzyme [41]. Mice, which lack that PKC ␥, display normal responses to acute pain stimuli, but do not display the exaggerated response to noxious stimuli usually seen after partial sciatic nerve section [42]. This implies that PKC ␥ plays a role in the hyperalgesia of neuropathic pain. The enzyme also may play a role in opioid-induced hyperalgesia and opioid tolerance. Ordinarily, repeated intrathecal injections of a selective µ-receptor agonist in the spinal fluid of a mouse will be associated with an uncoupling of the MOR from its G-proteins. Because Gproteins mediate at least some of the µ agonist’s analgesic effect, the uncoupling leads to tolerance. Neurons from mice that lack PKC ␥ fail to exhibit this desensitization of the MOR in vitro. Specific inhibitors of PKC also diminish the uncoupling of the MOR from the G-proteins [43]. The same phenomenon is seen in whole animals. Mice that lack the PKC ␥ gene fail to exhibit opioid tolerance [44]. One theory of opioid tolerance proposes that the internalization of the MOR allows a resensitization (ie, blunts opioid tolerance). There is evidence that PKC ␥ inhibits the internalization of MOR. This may be one of the mechanisms by which PKC ␥ desensitizes MOR and has a role in the development of acute tolerance [45].

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Nitric oxide is another important component of the effector pathway of hyperalgesia. It is an unusual effector of neuronal activity. As a gas, it diffuses readily within and between cells. Because its synthesis in vitro in response to interferon-gamma is increased in the monocytes of patients with complex regional pain syndrome, it is conceivable that it may play a role in the spread of pain from the initial site of injury [46,47•]. Nitric oxide generation is controlled by the enzyme nitric oxide synthase. Mice deficient in magnesium exhibit hyperalgesia, probably resulting from enhanced activity of the NMDA receptor, in which the channel is ordinarily blocked at resting potential by a magnesium atom. As might be expected, the hyperalgesia of these mice is reversible by the administration of NMDA antagonists. The hyperalgesia also may be reversed by specific inhibitors of nitric oxide synthase [48]. As mentioned previously, other links in the pain perception pathway mediate pain perception and opioid tolerance. The same is true in the case of nitric oxide, but the details are more complicated. Nitric oxide exists in several isoforms, at least two of which are important in pain modulation. Neuronal nitric oxide synthase type 1 (nNOS-1) is the predominant supraspinal form of the enzyme, and neuronal nitric oxide synthase type 2 (nNOS-2) is the predominant form in the spinal cord. Inhibition of these isoforms yields opposite effects. Down-regulation of nNOS-1 by antisense probes prevents the development of morphine tolerance, but down-regulating nNOS-2 actually blocks morphine analgesia [49]. Which system predominates in human disease has not been discovered [50•]. For years, pain clinicians have learned that opioids act centrally, and cyclooxygenase (COX) antagonists work peripherally. Neither statement may be completely true. There is ample evidence that MOR is expressed in inflamed tissue, and that peripherally applied opioids may decrease pain [51–53]. Perhaps more surprising is that COX antagonists may have a central action and may be involved in opioid tolerance. Spinal doses of COX antagonists may prevent or reverse opioid tolerance, even in doses too low to have a direct impact on pain-related behavior in nontolerant animals [54,55]. Opioid antagonists administered in ultra low doses have analgesic effects and may reverse or prevent opioid analgesic tolerance. Crain and Shen [56••] have theorized that there are two effector pathways that are set into motion by binding of the opioid agonist to the MOR. One pathway, the one we think of when we think of opioid action to reduce pain, is inhibitory, and the other is actually excitatory. The latter appears to be more sensitive to the action of opioids; opioids in concentrations several orders lower than that needed to inhibit pain may increase pain perception. Similarly, ultra low doses of opioid antagonists do not simply fail to block opioid effect; they may be powerful analgesics. Moreover, co-administration of ultra low doses of naltrexone may prevent or reverse opioid tolerance and dependence [56••]. It appears that GM1

ganglioside is an important part of the switching mechanism from opioid analgesia to opioid hyperalgesia. Mice deficient in GM1 ganglioside are particularly sensitive to the analgesic effects of morphine, and have diminished analgesic tolerance on repeat [57]. Cholera toxin B is a potent inhibitor of GM1 ganglioside activity [58]. It reduces opioid tolerance and seems to be far less dosecritical than opioid antagonists to accomplish this [59]. It has not been reported in human trials. The classical model of opioid analgesia posited that ongoing opioid stimulation led to uncoupling of the receptor from its effector pathway, internalization of the receptor, and consequent signaling desensitization [28•]. Some recent discoveries call that model into question. A key finding was that morphine, unlike enkephalins and etorphine, does not cause significant internalization of the µ opioid receptor [60]. Clearly, MOR signaling differed among opioid agonists and was dissociated from the internalization of the receptor. Moreover, internalization of the ligand and receptor did not necessarily commit them to subsequent degradation. The receptor might be dephosphorylated and recycled to the cell surface [61,62]. Unexpectedly, co-administration of morphine with subanalgesic doses of the powerful µ opioid agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol] enkephalin (DAMGO) causes internalization of the MOR and reduced tolerance to morphine [63]. It is hypothesized that DAMGO receptors drag morphine-bound receptors into the cell with them, leading to the recycling of the MOR to the cell surface and reduced tolerance. Opioid receptors can form into homooligomers and hetero-oligomers. This recent discovery promises new opportunities in elucidating the cause and control of opioid tolerance [64••].

Clinical Use of Opioids Although the basic science of opioids is progressing rapidly, the clinical application is advancing at a much slower pace. Pain is difficult to measure, and funding is lacking for many of the basic clinical trials that need to be performed to answer persistent questions. Nonetheless, some doubleblind, randomized trials are available to guide therapy. It seems that we can put to rest a dictum that has been mistaught to medical students for decades. Contrary to the tradition, the use of opioids in the emergency room does not delay or obscure the diagnosis of a patient with acute abdominal pain. A meta-analysis of clinical trials in adults, and a prospectively randomized, placebo-controlled trial in children show no benefit of withholding opioid analgesia as the diagnostic workup proceeds [65,66••]. We hope to see an end to the withholding of opioids in this setting, a process that has been solicitous in intent, but dolorous in effect. Another myth from the 20th century that may be discarded in the 21st century concerns the opioid of choice for patients with pancreatitis or who are recovering from biliary tract surgery. The classical teaching was that, unlike

Opioids: A Review • Chevlen

Table 3. Debunking meperidine Meperidine's metabolite may cause seizures There is no evidence that meperidine is preferable for biliary or pancreatic pain Intramuscular meperidine has no advantage compared with intravenous meperidine Used by patient-controlled analgesia, morphine yields better analgesia with fewer side effects than meperidine

morphine, meperidine does not raise the pressure of the sphincter of Oddi; therefore, meperidine was the preferred agent for these patients. There is no evidence to support such a preference. All opioids can raise pressure of the sphincter of Oddi. No comparative studies or outcome studies support the use of one opioid drug over another, although the risk of seizures with repeated doses of meperidine tilts the judgment toward the use of morphine [67]. Another myth concerning meperidine that can be discarded is that intramuscular (IM) injections of the drug give longer lasting analgesia than intravenous (IV) injections. During the first half-hour after an IM injection, the serum level of meperidine rises and that of an IV injection falls. However, after that, the pharmacokinetics of the two routes are indistinguishable [68,69]. Because IM injections may be painful and have other local complications, there does not seem to be an advantage for that route of therapy in a patient who already has established intravenous access. Finally, a randomized clinical trial of patientcontrolled analgesia post-operatively showed no advantage for meperidine compared with morphine. Morphine proved to be more effective as an analgesic. It also was associated with less dryness of mouth and less impairment of the ability to concentrate [70] (Table 3). Another clinical trial questions the drug of choice for the initial treatment of postherpetic neuralgia (PHN). Although the availability of the topical lidocaine patch has offered a new approach to the problem, many patients still require systemic therapy for pain control. Traditionally, that therapy has been a tricyclic antidepressant (TCA) or an antiepileptic. A randomized double-blind, placebo-controlled, crossover trial challenged the validity of that approach. In random order, patients with PHN were sequentially prescribed morphine, nortriptyline, or placebo for approximately 8 weeks each. Patients who did not tolerate morphine were switched to methadone; those who did not tolerate nortriptyline were switched to desipramine. The reduction in pain intensity from the administration of opioids was greater than that from a TCA, with a P value of 0.06 (to call such a P value insignificant is a venerable, but ultimately arbitrary scientific custom). Pain relief from one drug class did not correlate with pain relief from the other drug class. Although opioids had no impact on cognitive function, TCA therapy caused a statistically significant, but clinically trivial decline in cognitive function. Among patients completing all three treatments, significantly more preferred opioids to TCAs [71].

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The classic adverse effects of opioids are well known, and include transient respiratory suppression, somnolence, nausea, and constipation. Less appreciated is the endocrine effect of long-term opioid therapy. The vast majority of patients receiving intrathecal opioids experience hypogonadal hypogonadism. This is not a result of the pain itself; these hormonal abnormalities were not seen in similar patients who had not received opioid therapy. The endocrine defect may cause erectile dysfunction in men and irregular menses or amenorrhea in premenopausal women. Men and women may suffer diminished libido [72,73]. At the time of this writing, there is no published report of a similar effect in patients with pain taking oral opioids, but the unpublished observation from the author’s own practice is that the majority of men treated with opioids for chronic pain suffer from hypogonadism. Most benefit from androgen replacement therapy. This prevalence of hypogonadism in male patients with pain who are administered oral opioids is corroborated by the experience of Pakistani heroin addicts. In that population, there was universal hypogonadism [74]. The author recommends that all men and premenopausal women receiving chronic opioid therapy have an endocrinologic evaluation and treatment if hypogonadism is detected. Until opioids or opioid-containing combinations with better therapeutic indices are developed, the task of the clinician using opioids to treat pain will be one of side-effect management. In this regard, opioid therapy is unlike most other pharmacotherapies. In most clinical situations, the clinician who encounters a significant side effect of drug therapy is well advised to discontinue that particular drug and replace it with another from a different class. Unfortunately, in pain medication, there is seldom a better or alternative class of drug than opioids for moderate to severe pain. Thus, the pain clinician must add other drugs to counter the side effects induced by the opioids. The first side effect that concerns many patients is drugrelated sleepiness or fatigue. In many cases, the side effects diminish spontaneously after several days. However, in those cases in which they do not, there are several therapeutic options. The first is to add a psychostimulant (eg, methylphenidate or amphetamine) [75]. Adding methylphenidate to a marginally effective morphine regimen allows for dose escalation to levels of opioid that can relieve pain as it reduces sedation [76]. The patient may be getting more than the reduction of sedation and ease of opioid dose escalation from the psychostimulant. The psychostimulant may be acting directly to diminish pain. In mice, even low doses of d-amphetamine or methylphenidate enhance analgesia in the formalin test [77]. Psychostimulants are not the only class of drugs that may be used for this benefit. The author’s unpublished experience is that modafinil can accomplish the same reversal of sedation without the anxiety that is sometimes seen with methylphenidate or d-amphetamine. A small case series also suggests that the oral centrally acting

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acetylcholinesterase inhibitor donepezil (approved by the Food and Drug Administration for the treatment of Alzheimer's disease) also can reverse opioid-induced sedation [78]. The management of nausea and vomiting that accompany opioids in the treatment of acute pain is a greater problem than it is with chronic pain. A number of different regimens have been subjected to prospectively randomized, double-blind clinical trials. A study of post-operative nausea and vomiting (PONV) associated with patient-controlled morphine analgesia showed that droperidol and ondansetron were equally effective [79]. This result was contrary to that of an earlier study, which showed a comparative benefit for ondansetron [80]. The administration of low-dose propofol proved ineffective at preventing PONV in patients who received spinal morphine plus bupivacaine during major arthroplasty [81]. A different population was used to compare the efficacy of IV ondansetron for opioid-induced nausea. The patients in this study did not have surgery. Ondansetron proved more effective than placebo in these patients. Several non-traditional approaches to opioid-induced nausea and vomiting have been reported. A prospectively randomized trial compared acupressure bands applied to the so called P-6 point (on the palmar side of the wrist) with placebo bands similarly applied. All of the patients in this study were receiving epidural morphine after undergoing a caesarian section. The patients receiving the active treatment had a significantly lower incidence of nausea [82]. A meta-analysis corroborates this report, but notes that the benefit of acupressure for PONV does not extend to children [83]. The scientific difficulties associated with acupuncture trials also may apply to acupressure trials, but it is difficult to ignore statistically significant results involving a therapy with no apparent risks [84]. Ginger is used as a folk remedy for nausea. However, a double-blind, randomized clinical trial showed that it had no benefit in the prevention of PONV [85]. Constipation remains a major problem for patients who are taking opioids. Unlike many other adverse effects of opioids, this one does not improve with time. The use of an oral opioid antagonist to block the gut effect of the drug is attractive. Unfortunately, clinical trials showed that oral naloxone blocked analgesia as well as constipation [86]. A related drug, methylnaltrexone, seems more promising. It is the first peripherally acting opioid antagonist. Administered intravenously or subcutaneously, it reduces opioid-induced constipation [87,88]. Actual clinical use of this drug or a congener awaits a more convenient route of administration. Until that happy day, few clinical trials can supplement individual experience in guiding the prevention and treatment of opioid-induced constipation. Patients who experience uncontrollable constipation when they are administered chronic oral morphine therapy may do better if treated with transdermal fentanyl. A sequential treatment study that switched patients from sustained-release mor-

phine to transdermal fentanyl found that the consumption of laxatives dropped significantly without a change in the success of defecation [89]. Another trial using an openlabel, crossover design found oral morphine and transdermal fentanyl to be equally effective in relieving cancer pain; however, the latter was significantly less likely to cause constipation [90]. Polyethylene glycol 3350/electrolyte solution has been compared with lactulose in the management of opioid-induced constipation. It is more effective than lactulose in promoting defecation and is less likely to cause flatulence. It also may be more cost effective [91,92]. Unfortunately, the benefit of the commonly prescribed agents senna and docusate, or their combination, has not been compared with that of lactulose or polyethylene glycol 3350/electrolyte solution.

Conclusions For most of the 200 years since Sertürner, progress in the clinical use of opioids has depended on physicians’ experiences in treating people in pain and, to a far lesser extent, on scientifically designed clinical trials. The clinical developments in the next decade (to predict the events of the coming century is arrant) likely will reflect the discoveries of basic scientists and pharmaceutic chemists. Thus, we may look forward to substantial breakthroughs in the science and to gratifying improvements in our ability to relieve the suffering of those who come to us for help.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Pert C, Snyder S: Opiate receptor: demonstration in nervous tissue. Science 1973, 179:1011–1014. 2. Brady A, Limbird L: G protein-coupled receptor interacting proteins: emerging roles in localization and signal transduction. Cell Signal 2002, 14:297–309. 3.•• Pasternak G: The pharmacology of mu analgesics: from patients to genes. Neuroscientist 2001, 7:220–231. There is only one µ opioid receptor gene, yet the pharmacologic profiles of opioids differ. There is incomplete cross-tolerance among opioids. Animal models may be completely resistant to one opioid, but sensitive to others. Why? The answer is splice variants of the µ opioid receptor. The old dogma that one gene is expressed as only one protein is dead. 4. Han S, Cho Y, Kim C, et al.: Mu-opioid agonist-induced activation of G-protein-coupled inwardly rectifying potassium current in rat periaqueductal gray neurons. Neuroscience 1999, 90:209–219. 5. Loh H, Smith A: Molecular characterization of opioid receptors. Annu Rev Pharmacol Toxicol 1990, 30:123–147. 6. Reisine T, Bell G: Molecular biology of opioid receptors. Trends Neurosci 1993, 16:506–510. 7. Darland T, Heinricher M, Grandy D: Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more. Trends Neurosci 1998, 21:215–221. 8. Okuda-Ashitaka E, Ito S: Nocistatin: a novel neuropeptide encoded by the gene for the nociceptin/orphanin FQ precursor. Peptides 2000, 21:1101–1109.

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