Treatment of Pain in Patients with Addiction
Peggy Compton
Friedhelm Sandbrink
Martin D. Cheatle
Substance use disorder (SUD), formerly called substance abuse, dependence, or addiction, is a prevalent chronic disease in our society, not only with implications for the health and quality of the life of the sufferers but also with often devastating consequences for the families and communities in which they live and for society. Perhaps unlike any other chronic illness, SUD has meaningful effects on all aspects of the pain experience, ranging from its perception to its management. Specifically, the neurologic and behavioral states associated with the disease tend to worsen the pain presentation and mitigate the efficacy of therapeutic interventions. These complications become particularly apparent in the case of opioid use disorder (OUD), where the abused substance is also a primary analgesic used to treat moderate to severe pain. The development of opioid tolerance, physical dependence, hyperalgesia, and/or relapse are all challenges clinicians face when attempting to manage the pain of persons with OUD.
This chapter provides a brief overview of SUD, conceptualizing it as a chronic, relapsing neurologic disease for which evidence-based treatments exist, however, with access to these treatments limited in part due to negative societal perceptions of the illness. The overlap in neurobiologic systems in pain and SUD is considered, and how the presence of an SUD in general, and OUD specifically, can affect the experience of pain is discussed. Finally, principles of acute and chronic pain management for the patient with SUD is outlined, differentiated by whether the patient is actively using, on medication-assisted therapy (MAT; i.e., methadone, buprenorphine, naltrexone), or in drug-free recovery. Evident in these recommendations is the understanding that effectively and thoughtfully treating pain in the patient with SUD concomitantly benefits the recovery process regardless of the state of disease progression.
Substance Use Disorder
Misusing and abusing drugs and alcohol is endemic in the United States. The most recent national surveys suggest that approximately 8% (or 20 million) of Americans older than 12 years met diagnostic criteria for an SUD in the past year.1 Being legal and readily available, not surprisingly, three quarters of these individuals meet criteria for alcohol use disorder (AUD). Among those with an illicit drug use disorder, the most common drug is marijuana (4 million people), followed by an estimated 2.1 million people with an OUD, which includes 1.8 million people with a prescription pain reliever use disorder and 0.6 million people with a heroin use disorder.1 There is good evidence to suggest that the prevalence of SUD is higher in patients seeking medical care secondary to the toxic effects of the drugs themselves and/or the risky behaviors associated with the disorder.2,3,4,5
Like chronic pain, addiction is an extremely complex human condition, with strong behavioral and social components, that cannot be entirely understood by analyzing its physiology. SUD is defined as a chronic, relapsing disorder that is characterized by (1) a compulsion to seek and take drugs, (2) loss of control over drug intake, and (3) emergence of strong negative emotional states (e.g., dysphoria, anxiety, and irritability) when access to the drug is prevented (Table 32.1).6 The occasional, limited, recreational use of a drug is clinically distinct from the loss of control over drug intake and the emergence of compulsive drug-seeking behavior that characterize SUD.7 Because the disorder is primarily evident in behaviors, it is one of the few conditions in which the sufferer is the disease, as reflected in the pejorative labels ascribed to him or her (i.e., “drunk,” “druggie,” “addict,” “lush”).
Like all chronic disorders, SUD is never “cured,” but it can be effectively managed with lifestyle changes and, in some cases, medication. Similar to other chronic conditions, there are demonstrable pathophysiologic changes underlying the disorder, which, in the case of addiction, reside in subcortical and cortical neural pathways underlying reward and memory and, ultimately, the prefrontal cortex, driving behavior (Fig. 32.1). Without treatment, the disease will predictably progress and result in disability and ultimately death. Known risk factors for SUD in both patients with pain and in those without pain include a prior history of alcohol and/or illicit drug abuse (including nicotine addiction), a family history of substance abuse or SUD, a history of mood or anxiety disorder, early onset (age <14 years) of alcohol or drug use, a history of child sexual abuse or child neglect, involvement in the legal system, and significant psychosocial stressors.8,9 Furthermore, as with all chronic diseases, SUD is characterized by exacerbations (or relapses) over time, often at times of interpersonal or intrapersonal stress, and treatments are most effective when ongoing.
Adopting a chronic illness model for SUD provides the foundation for effective treatment; however, this model is inconsistent with societal perspectives. For example, SUD has been conceptualized as a moral failing, such that those who engage in problematic drug and alcohol use are often described as lacking honorable character or moral fortitude (i.e., “just say no”). Also, in the United States, illicit drug use is classified as a criminal behavior, with punishment, including incarceration, being the societal approach to treatment. Unfortunately, both the moral and criminal attributions to SUD result in significant shame and stigma for the sufferer, making them less likely to seek treatment and further isolating them from therapeutic supports. These negative perspectives
are reflected in the relative paucity and marginalization of SUD treatment services in the United States, such that in 2016, only about 1 in 10 people (10.6%) aged 12 years or older who needed substance use treatment were able to receive it.1
are reflected in the relative paucity and marginalization of SUD treatment services in the United States, such that in 2016, only about 1 in 10 people (10.6%) aged 12 years or older who needed substance use treatment were able to receive it.1
TABLE 32.1 Indicators of Substance Use Disorder | |||
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 FIGURE 32.1 Neuroanatomy of substance use disorders. VTA, ventral tegmental area. |
Fortunately, evidence-based treatments for SUD exist, and as a result of the current opioid abuse crisis, are becoming increasingly integrated into acute and primary care settings. For drugs of abuse with significant physiologic withdrawal syndromes (i.e., alcohol, opioids, benzodiazepines), treatment often begins with a taper or detoxification with a long-acting substitution agent. However, it is important to appreciate that detoxification in and of itself is not a treatment for SUD; it simply readies the patient for the cognitive, behavioral, and group support interventions necessary to mitigate disease progression. Opioid medications may be utilized as adjuncts to treatment in the case of AUD (naltrexone) and should be routinely offered to all patients with OUD (methadone, buprenorphine, naltrexone) to allay craving and withdrawal; in all cases, medications to treat underlying psychiatric disorders are indicated. Related to previous stressful or traumatic experiences, especially those occurring in childhood, individual or group psychotherapy can be highly beneficial for patients in whom adverse events are an issue, but access to and reimbursement for these services can be limited.
Clinical Implications of Substance Use Disorders on Pain
Pain and SUD are not unrelated phenomena, and this overlap becomes significant at the clinical level. Pain and drug reward share common neuroanatomical and neurochemical substrates, and the physiologic sequelae of SUD (i.e., tolerance, dependence, and altered stress response) have clear effects on pain management. Drugs of abuse often have inherent analgesic properties, yet SUD can bring with it mood states, behaviors, and social losses that worsen the pain experience. The clinical intersection of pain and SUD is particularly complex in the case of OUD, as opioids have rewarding, analgesic, and hyperalgesic activity. Furthermore, accumulating genetic data suggest that pain severity, opioid analgesia, and OUD may share similar patterns of gene expression, which become evident in the response of the individual patient to a painful stimulus.
NEUROBIOLOGIC OVERLAP BETWEEN PAIN AND ADDICTION SYSTEMS
It is not surprising that pain and SUD responses are related in that both are modulated by the activity of the same neuropeptide—the opioids at the opioid receptor. Whether administered endogenously or exogenously, opioids engender both pain relief and psychoactive reward, the latter of which provides the neurobiologic foundation for SUDs. All drugs of abuse, either directly or indirectly, activate opioid reward systems, which in individuals at risk can result in the compulsive behaviors diagnostic of SUD.
Of relevance to pain and pain treatment, the neurobiology of SUD is often characterized by two incompletely understood yet related allostatic states: tolerance and physical dependence. These neuroadaptations may be evident not only in those brain systems in which drugs of abuse exert direct actions but also in brain systems that oppose the actions of the drug.10 Importantly, the simple presence of these adaptations in the nervous system does not infer meeting the diagnostic criteria for SUD. Any individual using alcohol or opioids on a regular basis will become tolerant to or physiologically dependent on the effects of the drug; it is simply a neurobiologic outcome of drug exposure. As noted earlier, SUD is identified by a cluster of aberrant patterns of behavior that, although partially motivated by these physiologic changes, is evident in much broader functional domains (see Table 32.1).
Tolerance
Ongoing use of substances of abuse often results in the development of drug tolerance, even when they are used for analgesic purposes, which is defined as a reduction in response to a given dose of drug after repeated administration.10,11 The neuroadaptations associated with tolerance counter the acute drug effects to maintain system-level homeostasis. A theoretical explanation for the processes underlying tolerance is offered by the opponent process theory of acquired motivation.12,13 Reflecting homeostatic assumptions, the theory describes how, over the course of repeated exposures to a stimulus, a counteracting or opposing emotional or physiologic response develops, which eventually accounts for habituation to the stimulus and becomes the predominant state in its absence. In the case of drug reward, the model predicts that in order to maintain a “normal” or homeostatic level of reward system activity, “antireward” systems are recruited to counteract drug effects, which become stronger with each exposure and extinguish more slowly than the original response.14,15 Upon abrupt drug withdrawal, antireward or dysphoric processes are revealed. As described in the following discussion, analogous opponent processes are theorized to underlie the development of opioid-induced hyperalgesia (OIH).
Physiologic tolerance involves adaptations that occur both at the site of drug action and in systems distal to the site of drug action.16,17,18 Because drugs typically act at selective receptors, tolerance has been conceptualized as a functional “uncoupling” of the receptor from its effector response (opening or closing an ion channel, initiating second messenger systems); in other words, a certain proportion of receptors are rendered less functional or nonfunctional, thus making the drug less effective.18,19 Clinically, the resulting tolerance provides a certain amount of protection for the user, such as with the respiratory depressant effects of opioids or the anesthetic effects of ethanol. However, tolerance does not develop to all physiologic drug effects; for example, in the case of opioids, tolerance to opioid-induced constipation and opioid-induced androgen deficiency does not develop over time.20,21
Dependence
A related consequence of chronic drug use is physiologic dependence, defined as a physiologic adaptation to the continuous presence of a drug that results in symptoms of withdrawal
when the drug effect significantly diminishes or stops.22 Physical dependence occurs not only to drugs with reward potential, such as opioids and benzodiazepines, but also to those with little or no reward potential, such as α2-adrenergic agonists (e.g., clonidine), β-blockers, and tricyclic antidepressants. It is associated with a drug class-specific withdrawal syndrome that can be produced in persons with prolonged exposure to the drug by abrupt cessation, rapid dose reduction, decreasing blood level of the drug (e.g., due to administration of an enzyme inducing medication resulting in accelerated metabolism to the drug), and/or administration of an antagonist. When a drug blood level falls below a critical point, the adaptive changes associated with tolerance predominate and become profoundly nonadaptive.23 Suddenly unopposed by drug effects, the sources of tolerance become evident as the characteristic drug-specific withdrawal syndrome22,23 and a more generalized negative emotional state. Such negative emotional states include malaise, anxiety, dysphoria, emotional pain, loss of interest in natural rewards, and depression. These are common to withdrawal from all drugs of abuse, underlie drug craving and relapse, and are particularly relevant to the interface of SUD and pain.
when the drug effect significantly diminishes or stops.22 Physical dependence occurs not only to drugs with reward potential, such as opioids and benzodiazepines, but also to those with little or no reward potential, such as α2-adrenergic agonists (e.g., clonidine), β-blockers, and tricyclic antidepressants. It is associated with a drug class-specific withdrawal syndrome that can be produced in persons with prolonged exposure to the drug by abrupt cessation, rapid dose reduction, decreasing blood level of the drug (e.g., due to administration of an enzyme inducing medication resulting in accelerated metabolism to the drug), and/or administration of an antagonist. When a drug blood level falls below a critical point, the adaptive changes associated with tolerance predominate and become profoundly nonadaptive.23 Suddenly unopposed by drug effects, the sources of tolerance become evident as the characteristic drug-specific withdrawal syndrome22,23 and a more generalized negative emotional state. Such negative emotional states include malaise, anxiety, dysphoria, emotional pain, loss of interest in natural rewards, and depression. These are common to withdrawal from all drugs of abuse, underlie drug craving and relapse, and are particularly relevant to the interface of SUD and pain.
Analgesic Effects of Drugs of Abuse
As interactions between the neurobiology of pain and SUD are considered, it is notable that many classes of abused drugs have analgesic properties, recruiting ascending and descending pain pathways to diminish the perception of pain. The opioids are defined by their direct analgesic effects, and, at high doses, alcohol is a potent anesthetic and analgesic. The sedative hypnotics, particularly benzodiazepines, are used to treat painful muscle spasms and muscle spasticity secondary to upper motor neuron damage24 and are a standard anxiolytic adjunct for procedural sedation and analgesia.25,26 Central nervous system stimulants, such as cocaine and caffeine, produce and potentiate analgesia, presumably by increasing neurotransmitter activity in descending inhibitory pain pathways. Notably, all drugs of abuse provide reward via activation of subcortical opioid systems, and withdrawal from these substances increases sensitivity to pain.
Of current interest are the effects of cannabinoids on pain perception. Mao and colleagues27 have provided good preclinical evidence for an independent tetrahydrocannabinol (THC)-responsive antinociceptive pathway that is particularly effective for pain of neuropathic origin. Interference with glutamate release at the level of the dorsal root ganglia or periaqueductal gray is a hypothesized mechanism by which cannabinoids provide analgesia.28,29 Although clinical trials of cannabinoids in multiple sclerosis have suggested an analgesic benefit,30,31 human studies of cannabinoid-mediated analgesia have been limited by study size, heterogeneous patient populations, subjective outcome measures, and variable drug pharmacokinetics.32 Recent meta-analyses do not support that cannabinoids effectively treat acute,33 fibromyalgia34 or rheumatic pain.35 There are reports of moderate efficacy to treat cancer pain,36,37 although insufficient evidence for its use as an adjunct in this context.38 It is identified as a fourth-line analgesic for the management of neuropathic pain, behind the more effective antiepileptics, tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors (SNRIs), and lastly opioids.39,40 However, all reviews note that the paucity of well-controlled clinical trials on the analgesic efficacy of cannabinoids limits comprehensive evaluation of benefit.
EFFECTS OF SUBSTANCE USE DISORDER ON PAIN
SUDs bring with them physical and psychological consequences which serve to worsen or facilitate the pain experience, including autonomic arousal and negative mood states. These changes are related to both the discrete effects of certain classes of drugs and the effects of all drugs of abuse on reward-relevant systems. For example, important psychological sequelae characteristic of SUD, including sleep and psychiatric disorders, can contribute to the experience of pain and decrease the efficacy of analgesic interventions. SUD commonly co-occurs with mood and anxiety disorders41,42,43 which—if not corrected—can increase the perception of pain. Depression has been demonstrated to increase the discomfort associated with pain and to impair function in studies of patients with chronic pain, and pain symptoms frequently improve with effective antidepressant treatment, in particular the selective SNRI antidepressants which appear to have direct effects on pain pathways.44,45,46
Drug use in those with SUD is characterized by frequent and often rapid fluctuations in blood levels of the drug. Abused substances tend to be ingested in short-acting formulations and via routes with rapid onset (i.e., inhalation, intravenous [IV]) to boost psychoactive effect. These use patterns result in rapidly alternating states of intoxication and subtle (or sometimes fullblown) withdrawal. As detailed earlier, strong and persistent negative affective states accompany withdrawal from many drugs of abuse, including anhedonia, prolonged dysphoria, and irritability.47,48 Clearly, the negative feeling states associated with drug withdrawal can augment the subjective discomfort associated with pain.
Finally, and not insignificantly, the stress associated with interpersonal conflicts, role adjustments, and social support losses that characterize the lived experience of SUD can worsen the experience of pain, making the individual less able to manage or cope with discomfort, and to interfere with effective pain treatment engagement and implementation of active pain treatment modalities. The chaotic and drug-oriented lifestyle of the sufferer make it difficult to comply with prescribed pain management regimens and engage in pain reduction activities (i.e., exercise, mindfulness meditation). Empirical support for a worsened pain experience in individuals with active SUD has been demonstrated in the case of experimental pain; subjects currently using addictive drugs are significantly less tolerant of cold-pressor (CP) pain than matched drug-free ex-abusers regardless of whether the primary drug of abuse was a stimulant (cocaine) or an opioid.49
The development of SUD and chronic pain appear to share epigenetic mechanisms, underscoring the interrelated nature of these phenomena. In the case of alcoholism, epigenetic modifications in the amygdala have been demonstrated to contribute to the negative affective states characteristic of the allostatic changes associated with SUD,50 whereas cocaine intake appears to alter gene expression in reward-relevant pathways in the nucleus accumbens.51 Such epigenetic regulation may be especially significant during windows of neurodevelopmental vulnerability (prenatal, adolescence)52 and explain the link between early substance abuse and SUD later in life. In the case of chronic pain, there is evidence that inflammation and tissue or neural injury can induce epigenetic modifications in the central nervous system resulting in pain hypersensitivity,53 including allodynia and hyperalgesia. Portending overlap between epigenetic mechanisms that mediate both chronic pain and SUD, Descalzi and colleagues54 describe chronic pain-induced modifications in brain reward systems which are analogous to those induced by exposure to drugs of abuse.
EFFECTS OF OPIOID USE DISORDER ON PAIN
Because the opioid class of drug abused is also a primary pharmacologic tool for the treatment of moderate to severe clinical pain, the effects of SUD on pain become particularly significant in the case of individuals addicted to opioid drugs. As noted earlier, OUD and opioid analgesia are dependent on agonist activity at the µ-opioid receptor; the reinforcing and analgesic effects of morphine, for example, can be blocked by the
administration of µ-receptor antagonists and are absent in µ-opioid receptor gene knockout animal models. In that the same receptor is central to both SUD and pain systems, it is reasonable to expect that alterations related to the latter might be evident in individuals chronically exposed to opioids (agonists or antagonists) in the context of the former. Although drug reward and analgesia are distinct processes, opioids activate their shared anatomical substrate, inducing the previously described interrelated adaptations of tolerance and dependence. Individuals with OUD may seek psychoactive effects yet are not immune to the effects of these drugs on central and peripheral opioid-relevant pain systems.
administration of µ-receptor antagonists and are absent in µ-opioid receptor gene knockout animal models. In that the same receptor is central to both SUD and pain systems, it is reasonable to expect that alterations related to the latter might be evident in individuals chronically exposed to opioids (agonists or antagonists) in the context of the former. Although drug reward and analgesia are distinct processes, opioids activate their shared anatomical substrate, inducing the previously described interrelated adaptations of tolerance and dependence. Individuals with OUD may seek psychoactive effects yet are not immune to the effects of these drugs on central and peripheral opioid-relevant pain systems.
Early research in both human and animal models indicated that opioids are less rewarding in the presence of pain,55,56 suggesting that pain interfered with the reinforcing properties of the medication. This hypothesis is supported by reports from patients who say that opioids relieve their pain without psychoactive effects; furthermore, many patients experience dysphoria or other aversive feelings, rather than euphoria, when given opioids for their pain and often stop taking them for this reason alone. Nevertheless, based on our current understanding that a subgroup of patients treated with long-term opioids for chronic pain meet diagnostic criteria for OUD, the presence of pain cannot be considered a sufficiently protective factor against reward to occur and resulting OUD, particularly in those at risk.57,58
Genetics of Pain and Opioid Use Disorder
Individual differences in pain perception and opioid response have long been appreciated in the clinical setting, and genetic factors, which underlie these differences, are increasingly elucidated. For example, heritable differences in hepatic P450 isoenzyme activity affect both the amount of reward and analgesia received from an opioid. Individuals who are extensive “metabolizers” of opioids (i.e., those with high P450 activity) receive less analgesia and reward from a given opioid dose59,60,61 theoretically putting them at decreased risk for SUD but increased risk for unrelieved pain.62 Preliminary data suggest that these extensive metabolizers of opioids are less tolerant of experimental pain, possibly due to defects in the endogenous synthesis of opioids.63
The preclinical literature, primarily from the laboratories of Mogil et al.64,65 and Elmer et al.,66,67,68 shows that recombinant murine strains differ both in their baseline tolerance for pain and in the amount of reward or reinforcement they receive from opioids. Specifically, strains of animals with poor pain tolerance (i.e., C57, CXBK) find opioids to be highly reinforcing, whereas those with good pain tolerance (i.e., BALB/c, CXBH) receive little reinforcement from opioids.69,70,71 Furthermore, pain-tolerant murine strains receive robust opioid analgesia and demonstrate increased opioid receptor binding activity as compared to pain-intolerant strains.72
Investigators in both the pain and SUD fields have been focusing on polymorphisms in the µ-opioid gene receptor (OPRM) as candidates underlying phenotypes for pain sensitivity,73,74,75 opioid analgesic response,76 and SUD.77,78 Best characterized is the single nucleotide polymorphism A118G of the OPRM, such that normal human subjects with the variant allele have been shown to require almost twice as high as plasma level of morphine to achieve the analgesic response as those with the nonmutated allele.79,80 Other genes that have been linked to pain and opioid responses include those that code for the δ-opioid receptor, the capsaicinsensing vanilloid receptor,81 the neurotransmitter enzyme catechol-O-methyltransferase,82 and the melanocortin-1 receptor gene.83
Patients with OUD may present for pain care with untreated disease (actively using illicit opioids), on MAT (methadone, buprenorphine, naltrexone), or in drug-free recovery. Principles of pain treatment for each of these groups are presented in subsequent sections of this chapter. Outlined in the following discussion are the effects of illicit or prescribed opioid agonist use on pain responses of patients with OUD.
Tolerance
Tolerance occurs differentially to opioid analgesic and rewarding effects as well as to such adverse effects as respiratory depression, sedation, nausea, sleep disturbance, or constipation. As noted earlier, the presence of tolerance does not presuppose the presence of SUD and is simply an adaptive outcome secondary to opioid exposure. Opioid tolerance can be innate due to inherent biogenetic characteristics of the individual, or it can be acquired in response to ongoing opioid exposure. Acquired opioid tolerance may be due to both pharmacokinetic factors, such as changes in drug absorption and metabolism that reduce blood concentration, and to pharmacodynamic factors such as receptor desensitization or other density changes at the level of opioid receptors.84,85 Changes in central immune signaling and in N-methyl-D-aspartate (NMDA) receptor activity have been demonstrated in the development of opioid tolerance.86,87 As described earlier, behavioral opioid tolerance evident in mood and affect has been attributed to opponent adaptive processes in the mesocorticolimbic reward circuitry.88
The incidence of analgesic tolerance in clinical settings has not been well described. Animal studies suggest that tolerance to the analgesic effects of opioids occurs in some contexts but not in others.84 Human studies of the management of acute pain document the development of progressive tolerance to the analgesic effects of opioids when they are administered on a continuous basis over a period of several days.89 However, over longer periods of time (weeks to months), evidence for the continuing development of progressive opioid analgesic tolerance is mixed.90,91,92,93 Interestingly, persons on MAT for OUD do not appear to develop tolerance to the opioids; patients can remain on the same dose of methadone or buprenorphine for years without a diminution of treatment effect. However, patients with OUD, whether actively using or on agonist MAT, do clinically present with notable opioid analgesic tolerance and in cases of acute obstetric, surgical, or traumatic pain require much larger doses of opioids to achieve relief than do opioid-naive individuals.94,95,96
Physical Dependence
As is the case of opioid tolerance, physical dependence on opioids does not presume the active presence of SUD; persons with SUD on MAT are physically dependent despite being in a state of recovery, and individuals taking opioid analgesics on a regular basis can become physically dependent on medications without meeting the diagnostic criteria of SUD.97 Common symptoms of opioid withdrawal include autonomic signs and symptoms, such as diarrhea, piloerection, sweating, mydriasis, and mild increases in blood pressure and pulse, as well as signs of central nervous system arousal such as irritability, anxiety, and sleeplessness. The character and intensity of opioid withdrawal vary, depending on the dose and duration of opioid administration and a variety of host factors, including previous experience with withdrawal, prior long-term administration of opioids, and the patient’s expectations regarding withdrawal.98 These negative emotional states and stress-like responses during withdrawal have been ascribed to diminished function of the dopamine reward system as well as activation of certain brain stress neurotransmitters, such as corticotropin-releasing factor (CRF) and dynorphin.99
Craving for the medication is expected in the course of withdrawal, and pain—most often experienced as abdominal cramping, deep bone pain, or diffuse muscle aching—is common.100 Providing evidence for opioid withdrawal hyperalgesia, patients with chronic pain report intensified levels of their usual pain syndrome during withdrawal.101,102,103 In patients who are physically dependent on opioids, the use of short-acting opioids may result in intermittent withdrawal between doses, which may cause an increase in perceived pain.104,105
Opioid-Induced Hyperalgesia
Finally, it appears that OUD brings specific hyperalgesic changes to pain systems, which can further complicate the experience and management of pain. Extensive preclinical evidence demonstrates that at the same time opioids provide potent analgesia, they paradoxically set in motion molecular processes that eventually result in OIH. OIH is defined as increased sensitivity to pain resulting from opioid administration and characterized by increase in pain sensitivity to external stimuli over time and spreading of pain to locations beyond the initial pain site. Broadly conceptualized as an opponent process, the hyperalgesia induced by opioids is theorized to counter the analgesia these drugs provide. As with tolerance and physical dependence, OIH is not diagnostic of OUD; rather, it is an outcome of ongoing opioid exposure.
OIH has been best demonstrated in animal models, wherein pain-free rodents have significantly decreased nociceptive thresholds from baseline following single or repeated administration of opioids. These preclinical studies have shown that OIH generalizes across nociceptive stimuli (thermal chemical, electrical), opioid agent (heroin, fentanyl, morphine), and route of administration (IV, subcutaneous [SC], intrathecal [IT], intraperitoneal [IP], oral). The hyperalgesia is dose dependent (cumulative dose/cumulative exposure) and appears to resolve in a time course similar to its development, with increased magnitude of response correlated to its duration. It intensifies with antagonist precipitated withdrawal and worsens with repeated withdrawal episodes.106,107,108,109,110
Links have been hypothesized to exist between the neural mechanisms responsible for the hypersensitive negative emotional states associated with OUD and OIH.47,48 For example, evidence suggests that the stress system neuroadaptations associated with SUD may overlap with substrates of emotional aspects of pain processing in the amygdala.15,111,112 Supporting these links, opioid (and alcohol) withdrawal in animal models produce increased anxiety-like responses and hyperalgesia, both of which are blocked by CRF antagonists.113,114
Withdrawal Hyperalgesia
The phenomenon of hyperalgesia has long been recognized as a fundamental symptom of the opioid withdrawal syndrome in animal models of dependence,115,116,117,118,119 and although not extensively studied, hyperalgesia and spontaneous muscle and bone pain have long been considered cardinal symptoms of opioid withdrawal in humans.11,120 The time course, opioid dose-response relationship, and opioid pretreatment parameters of withdrawal hyperalgesia have been carefully characterized in preclinical models for over 30 years, such that it arises following single or chronic opioid exposure, can be detected up to 5 days following SC injection, and increases in intensity with pretreatment opioid dose or intrinsic efficacy.121,122
Heightened pain perception has been observed in persons during opioid withdrawal.123 Individuals with OUD maintained on either methadone or buprenorphine showed increased sensitivity to CP pain.124 Indeed, Ren et al.125 found that a hyperalgesic state can persist for up to 5 months in abstinent individuals with a history of OUD, and those with more pain sensitivity also displayed greater cue-induced craving at follow-up. Thus, OUD individuals with poor pain tolerance may suffer a more severe form of SUD, have difficulty tolerating the discomfort (pain) inherent in detoxification and early abstinence, and be more likely to relapse.
Opioid-Induced Hyperalgesia and Tolerance
The presence of hyperalgesia with ongoing opioid use provides an alternate conceptualization of analgesic tolerance. It is clear that similar systems are involved in the evolution of OIH and of opioid tolerance; however, the clinical and neurophysiologic relationships between opioid tolerance and OIH continue to be elucidated.16,17,18,19 As eloquently hypothesized by Colpaert126,127 and Célèrier et al.,128,129,130 that which appears to be opioid analgesic tolerance, and therefore increased opioid need, may in fact be an organismic response to an opioidinduced hypersensitivity to pain or “apparent tolerance.” Essentially, opioids lose their analgesic effectiveness in the face of decreased tolerance for pain. That OIH might contribute to the phenomenon of analgesic tolerance in the clinical setting is a paradigm-shifting idea; analgesic tolerance may reflect underlying neuroadaptive changes that reflect the development of hyperalgesia.
In an important series of early preclinical studies exploring the molecular mechanisms of hyperalgesia, Mao and colleagues131,132,133,134,135 demonstrated many similarities between opioid analgesic tolerance and OIH. These investigators provide credible evidence that the development of opioid analgesic tolerance via intermittent morphine dosing induces hyperalgesia, whereas animals made hyperalgesic via neuropathic injury concomitantly exhibit opioid analgesic tolerance (results replicated with heroin by Célèrier et al.129).
Mechanisms of Opioid-Induced Hyperalgesia
Various explanations for the development of OIH have been offered and include spinal, supraspinal, and cortical (learned) sites of action (Fig. 32.2).121,136,137,138,139,140,141,142 Mao and colleagues131,132 have demonstrated that the shared pathway for the development of morphine tolerance/hyperalgesia is activation of excitatory NMDA receptors on dorsal horn neurons, with subsequent intracellular increases in protein kinase C and nitric oxide. Like the hyperalgesia associated with neuropathic pain,132,141 OIH is conceptualized as a variant of central sensitization and thus prevented by NMDA receptor antagonism and calcium channel blockers.131,143,144,145,146,147 The latter finding has spurred interest in the potential utility of NMDA receptor antagonists (i.e., ketamine) as a means to treat OIH148,149,150,151 and complements the ongoing work of addiction scientists on the utility of these agents to reverse opioid tolerance and dependence.152,153,154,155,156
Alternatively, Vanderah and colleagues provide good preclinical evidence142 that opioids activate descending pain facilitation systems arising in the rostral ventromedial medulla (RVM),143 resulting in OIH.142,145,157 Specifically implicated are opioid-induced increases in levels of cholecystokinin (CCK), a pronociceptive peptide, in the RVM; these increased CCK levels appear to play a role in the development of opioid analgesic tolerance as well.158 It is suggested that CCK activity in the medulla drives descending pain facilitatory mechanisms, resulting in spinal hyperalgesic responses to nociceptive input141,142; notably, CCK is also involved in the opioid nocebo effect of hyperalgesia.159
Various spinal neuropeptides, distinct from excitatory amino acid systems, have also been implicated in the development of OIH. Over a decade ago, Simonnet’s laboratory showed that a single dose of parenteral heroin resulted in significant release of the antiopioid neuropeptide FF from the spinal cord in rats, an effect blocked by the subsequent administration of the opioid antagonist naloxone. This induced a hyperalgesia 30% below
threshold baseline.160 More recent animal work in Porreca’s laboratory has demonstrated increased levels of lumbar dynorphin, a κ-opioid agonist with pronociceptive activity, following sustained spinal opioid administration.137,141 Interestingly, the hyperalgesic effects of opioids have been reversed by the administration of an antagonist to the neurokinin-1 receptor, which is the receptor mediating the nociceptive neuropeptide substance P. Particularly active in pain of inflammatory origin, substance P involvement suggests a neuroinflammatory component to the development of OIH.161
threshold baseline.160 More recent animal work in Porreca’s laboratory has demonstrated increased levels of lumbar dynorphin, a κ-opioid agonist with pronociceptive activity, following sustained spinal opioid administration.137,141 Interestingly, the hyperalgesic effects of opioids have been reversed by the administration of an antagonist to the neurokinin-1 receptor, which is the receptor mediating the nociceptive neuropeptide substance P. Particularly active in pain of inflammatory origin, substance P involvement suggests a neuroinflammatory component to the development of OIH.161
 FIGURE 32.2 Theorized mechanisms of opioid-induced hyperalgesia. NMDA, N-methyl-D-aspartate. (Adapted from Angst MS, Clark JD. Opioidinduced hyperalgesia: a qualitative systematic review. Anesthesiology 2006; 104[3]:570-587.) |
A related inflammatory mechanism mediated by neuroimmune processes has been hypothesized in the development OIH.162 In this paradigm, peripheral immune cells activated in response to opioid administration are hypothesized to bind to astrocytes and induce specific classes of central proinflammatory (and therefore pronociceptive) cytokines, thus resulting in a state of heightened pain sensitivity.163,164,165,166,167,168 For example, within hours of heroin or morphine administration, mice demonstrate increased serum levels of interleukin (IL)-6,169 and splenocyte production of IL-1β, IFN-γ, IL-12, and TNF-α,170 effects antagonized by naltrexone.171 Proinflammatory consequences are suggested by parallel evidence for decreased expression of the anti-inflammatory cytokines, IL-10 and IL-4, following acute opioid exposure.170,172,173 Via toll-like receptors, opioids induce proinflammatory effects on spinal glial cells, which is thought to lead to increases in cytokines in the plasma.174,175 Reviewing the literature, Ossipov157(p320) commented that, “opioid-induced abnormal pain may share a molecular signature with pain of inflammatory origin.”
Finally, a conditioned component to OIH was demonstrated by Siegel and colleagues more than 30 years ago.176,177 A robust hyperalgesia was observed in animals receiving saline in an environment previously paired with morphine administration.176,177 This work showed that rats receiving acute morphine doses (3 to 9 doses separated by 48 hours) in a specific environment demonstrate significant hyperalgesia in the same setting as compared to rats receiving morphine unpaired with setting or saline control rats. Because conditioned responses to medications typically are opposite in direction to unconditioned drug effects, the learned responses were ascribed a causal role in the development of drug tolerance.
Clinical Evidence of Opioid-Induced Hyperalgesia
That hyperalgesic pain responses accompany OUD clinically is not a new idea. In an early essay describing his clinical observations on patients injecting morphine on a daily basis, physician and author Clifford Albutt178 asked, “Does morphia [sic] tend to encourage the very pain it pretends to relieve?” He continues, “I have much reason to suspect that a reliance upon hypodermic morphia only ended in a curious state of perpetuated pain.”178 As noted, descriptions of OIH have been principally established in animal models, making it difficult to extrapolate to the clinical setting. Not only is pain a much more highly modulated experience in humans than in animals, but it is not entirely clear how pain tolerance in humans (point of subjective intolerance of pain, an indicator of hyperalgesia) maps onto putative pain threshold or perception (point at which animal withdraws tail, jumps, on hotplate) in animals. Furthermore, the development of OIH has been better characterized in animals without pain or with acute pain; thus, its effect and relevance in the common condition of chronic pain remain incompletely described.
Evidence for OIH in humans has primarily been demonstrated in three distinct populations: patients with OUD on MAT (methadone, buprenorphine), patients administered opioids during the surgical period, and healthy volunteers administered opioids acutely and then evaluated with experimental pain assays. Less common, but of increased interest in the era of the prescription opioid crisis, are data to support the presence of OIH in patients with chronic pain on opioid therapy; the degree to which prescribed opioids worsen outcomes in chronic pain patients is an important area of investigation (see Fig. 32.3 for differential diagnoses of requests for increase opioid medication).
Patients on Medication-Assisted Therapy. Over 50 years ago, Martin and Inglis179 described significantly lower tolerance for CP-induced pain in a sample of incarcerated opioid-abusing women in comparison to matched nonaddicted controls. Ho and Dole180 found that both methadone-maintained (MM) and drug-free opioid-addicted individuals had significantly lower thresholds for CP pain than did matched nonaddicted sibling controls. Subsequent work supports that, prior to methadone dosing, CP pain threshold (defined as time when cold sensation becomes painful) does not differ between MM and drugfree individuals with OUD but is significantly lower for MM patients in comparison to matched normal controls.49,181,182 Under the same conditions, MM patients’ CP pain tolerance (defined as time when pain becomes subjectively intolerable) is less than that in both matched drug-free patients with OUD49 and matched controls.181,182,183 With respect to perceived pain severity, Schall and colleagues184 found no difference between MM and control subjects in their perception of pressure pain (measured on a scale of 1 to 10) immediately prior to methadone dosing.
Across nociceptive stimuli, methadone patients reliably demonstrate poor tolerance for experimental pain and are,
on average, between 42% and 76%, less tolerant of CP pain than are normal controls matched on age, gender, and ethnicity.124,181,182,185,186 Pilot data suggest that degree of hyperalgesia may vary with the intrinsic activity of the opioid maintenance agent, such that patients maintained on the partial agonist buprenorphine are less hyperalgesic than those maintained on methadone, a full agonist.124 Note that all these data are correlational in nature, resulting in controversy as to whether or not the diminished tolerance in pain noted in persons on MAT for OUD is in fact “opioid induced” (Table 32.2). It is possible that patients prone to OUD are pain intolerant by nature, which is therefore present while on MAT.
on average, between 42% and 76%, less tolerant of CP pain than are normal controls matched on age, gender, and ethnicity.124,181,182,185,186 Pilot data suggest that degree of hyperalgesia may vary with the intrinsic activity of the opioid maintenance agent, such that patients maintained on the partial agonist buprenorphine are less hyperalgesic than those maintained on methadone, a full agonist.124 Note that all these data are correlational in nature, resulting in controversy as to whether or not the diminished tolerance in pain noted in persons on MAT for OUD is in fact “opioid induced” (Table 32.2). It is possible that patients prone to OUD are pain intolerant by nature, which is therefore present while on MAT.
 FIGURE 32.3 Differential diagnoses for patient requests for increased opioid. Pseudoaddiction refers to drug-seeking behaviors driven by unrelieved pain. Therapeutic dependence refers to drug-seeking/hoarding behaviors related to anxiety about being without. |
Surgical Patients. Increasing evidence suggests that opioids administered in the intraoperative period induce postoperative hyperalgesia in patients without OUD undergoing surgery191,192,193 and perhaps in a dose-dependent manner. Data show that in patients undergoing various abdominal surgeries, postoperative reports of pain severity at rest and/or opioid consumption were significantly higher in those patients receiving IT or IV short-acting opioids (fentanyl and remifentanil) during surgery in comparison to those receiving placebo192,193 or low-dose opioids.191,194,195,196 The hyperalgesia is most pronounced early in the postoperative period (24 hours) and with high-dose remifentanil administration; patients receiving high-dose intraoperative opioids utilized approximately 18 mg more of morphine sulfate during the postoperative period and had larger margins of wound hyperalgesia than those in patients with lower intraoperative opioid exposure. The hyperalgesia was minimized if the cumulative intraoperative opioid dose was kept less than 40 µg/kg; if coadministered with ketamine,197,198,199 magnesium,200 dexmedetomidine,201 pregabalin,202 propofol,203 nitrous oxide, and clonidine; or if tapered slowly. In that it is elicited with the abrupt offset of intraoperative remifentanil infusion suggests that rather than OIH, withdrawal hyperalgesia may be the source of increased sensitivity to pain. These findings have spurred current interest in evaluating opioid-sparing peri- and intraoperative procedures, such as preoperative administration of gabapentinoids; coadministration of nonopioid analgesics including nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, ketamine, magnesium, propofol, nitrous oxide, and clonidine; and nonpharmacologic strategies to minimize postoperative OIH.24,25
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