Summary by Mahreen Raza, MD, and Petros Levounis, MD, MA, FASAM
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Based on “Principles of Addiction Medicine” Chapter by Rollin M. Gallagher, MD, MPH, George Koob, PhD, and Adrian Popescu, MD
Chronic pain is a common and costly chronic illness. Treatment with opioid analgesics poses an additional challenge. Neural and glial networks regulating pain perception and behavior interact with emotional regulation and reward systems influencing addiction.
CHRONIC PAIN
The concept of acute and chronic pain as distinct entities has now been replaced with a continuum—from onset to cessation. Chronic nociceptive pain involves processes that include transduction/activation, transmission, modulation/augmentation, and perception. Chronic neuropathic pain is often independent of transduction and involves persistent activation, transmission, modulation/augmentation, and perception. In both, a number of biopsychosocial factors, including environmental context, meaning of pain, mood/affect, anxiety, catastrophizing, and social and cognitive attention/reinforcement, influence the neuroplastic changes in the central nervous system (CNS) that determine an individual’s experience of pain.
Pain Anatomy and Physiology
Wall and Melzak’s postulation of the gate theory of pain provided the first pathophysiologic model to explain pain perception and modulation. The complex mechanisms implicate multiple targets for treatments, which aim to reduce the stimulus itself, block the stimulus from reaching the spinal cord, or target CNS responses and pathologic neuroplasticity. To target all of these processes, integrated treatments are utilized.
The complex phenomenology of pain can be characterized as three major “stages,” including (1) nociception, the consequences of a brief noxious stimulus; (2) persistent and/or repeated nociception, the consequences of a prolonged or repetitive noxious stimulus leading to tissue damage and peripheral inflammation; and (3) the consequences of neurologic damage, including peripheral neuropathies and peripheral and central sensitization.
Stage 1: Nociception
a. Strong noxious stimulus (mechanical, thermal, or chemical) → nociceptors → depolarization of pain afferents (A delta and C fibers) → dorsal horn of the spinal cord → depolarization of second-order neurons → lateral and medial thalamus → somatosensory cortex → perception of pain
b. Projections from the medial thalamus → limbic system (anterior cingulate cortex and insular cortex) → emotional aspect of pain
c. Projections from medial thalamus → hyperresponse of second-order neurons → pain perception despite no increase in nociceptor input
Stage 2: Peripheral Sensitization
Noxious stimulus (intense or prolonged) → tissue damage and inflammation → “awakening” of nociceptors → spontaneous discharges → peripheral sensitization → activation of second messenger systems → influx of Ca++ ions → release of substance P → continued release of inflammatory mediators.
The balance of these excitatory and inhibitory processes at the level of spinal cord provides an explanatory basis for the gate theory of pain transmission.
Stage 3: Central Sensitization
In central sensitization, persistent noxious input sets off a process of enhancement of responsiveness in the dorsal horn neurons that continues independent of primary afferent drive. Central sensitization is thought to be responsible for the clinical presentation of secondary hyperalgesia (hyperalgesia in sites away from the site of initial injury) and allodynia (pain from stimuli that normally do not result in pain).
Maldynia is characterized by a lack of correlation between the intensity of a peripheral stimulus and the intensity of pain and also by pain that is spontaneous or triggered by innocuous physical or psychological stimuli. However, the development of stage 3 pain may also involve genetic, cognitive, and emotional factors, which remain to be clarified.
Recent brain imaging studies suggest that more rostral changes in the CNS also mediate sensitization. For example, changes in the hippocampus may sustain potentiation of an initial stimulus for up to a year, which can be reversed by placing laboratory mammals in a challenging novel environment. This finding supports a widely held clinical belief that stimulating, goal-directed activity and exercise suppress pain, enable improvements in functional ability, and even reduce the manifestations of central sensitization. This phenomenon supports the effectiveness of comprehensive rehabilitation programs in treating chronic pain. Similarly, regions in the cingulate gyrus have now been identified for modulating behavioral responses to pain, attention to pain, pain-induced fear, and learning and pain. Treatment thus involves a comprehensive approach that incorporates the patient’s biopsychosocial profile.
Pain and Emotions
Emotional states that activate sympathetic arousal, such as anxiety or anger, can increase acute pain and reactivate or worsen chronic pain. Thus, it follows that comorbid depression and anxiety disorders; certain personal traits, such as external locus of control and a tendency to catastrophize; and comorbid substance abuse may complicate the treatment of pain.
Historical Notes on Psychosomatic Concepts
Literature review demonstrates a strong association between depressive and anxiety disorders and chronic pain. The effects of environmental factors on the pathogenesis of both disorders may also be shared. Stress and trauma, implicated in both facial pain and depression, may alter the course of pain in subjects with existing pain. This could potentially reflect a genetic or other biologically mediated vulnerability to respond to stressful or traumatic events with psychological and pain-related symptoms.
Pain and Anxiety
The experimental and epidemiologic evidence points to a strong association between anxiety and pain, partly mediated by the amygdala. The “nociceptive amygdala” can be influenced by a wide range of environmental and internal stimuli. The emotional value the amygdala places on a particular memory is then fed back to the hippocampus, which integrates this information to either strengthen or weaken the memory. Thus, events associated with high emotional content tend to be remembered in greater detail.
Human imaging studies have found that the fusiform gyrus, prefrontal gyrus, and anterior cingulate gyrus are preferentially activated in response to fearful stimuli. The orbitofrontal cortex, which is involved in the evaluation of risk and reward and social norms, may also have a direct role in regulation of anxiety via its connection to the amygdala. These connections and their conditioning suggest the biologic basis for behavioral treatments in chronic pain, such as relaxation and biofeedback.
CLINICAL INTERFACE BETWEEN PAIN AND ADDICTION
Pain and drug reward share common neuroanatomical and neurochemical substrates, and the physiologic sequelae of addiction (i.e., tolerance, dependence, and altered stress response) have clear effects on pain management. Drugs of abuse often have analgesic properties, yet the disease of addiction brings with it malaise, mood states, behaviors, and social losses that exacerbate the pain experience. The clinical interaction of pain and addiction is particularly complex in the case of addiction to opioids, as these drugs appear to be imbued with both analgesic and hyperalgesic properties. Furthermore, accumulating genetic data suggest that pain, opioid analgesia, and opioid addiction may share similar patterns of gene expression.
Neurobiologic Mechanisms of Addiction
Like pain, addiction is an extremely complex human response, with strong behavioral components. Addiction can be defined as a chronic, relapsing disorder that has been characterized by (1) a compulsion to seek and take drugs, (2) loss of control over drug intake, and (3) emergence of a negative emotional state.
Addiction has been conceptualized as a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—that worsens over time and involves the brain reward and stress systems. Different theoretical perspectives from experimental psychology (positive and negative reinforcement frameworks), social psychology (self-regulation failure framework), and neurobiology (counteradaptation and sensitization frameworks) can be superimposed on the stages of the addiction cycle. These stages interplay to cause addiction.
Two components are hypothesized to comprise the allostatic break from homeostasis in addiction: underactivation of brain reward transmitter function and recruitment of brain stress (or antireward) systems. These systems (reward and stress) interact at all stages of the addiction cycle to potentiate such emotional dysregulation. Of relevance to issues of pain and pain treatment, the neurobiology of addiction often is characterized by two incompletely understood yet related allostatic states: tolerance and dependence.
Tolerance
Ongoing use of all psychoactive drugs with addiction potential results in the development of drug tolerance, which is defined as a reduction in response to a given dose of drug after repeated administration. The neuroadaptations associated with tolerance counter the acute drug effects to maintain system-level homeostasis.
Dependence
A related consequence of chronic drug use is dependence, which is an altered physiologic state in which an effect opposite to that of a drug becomes manifest when the drug is removed. Suddenly, unopposed by drug effects, tolerance manifests as (1) the characteristic drug-specific withdrawal syndrome and (2) a more generalized negative emotional state.
Neurobiologic Interface of Pain and Addiction
The development of aversive or negative emotional states that constitute negative reinforcers in addiction has been linked to two distinct neurobiologic processes: loss of function in the reward systems (within-system neuroadaptations) and recruitment of brain stress or antireward systems (between-system neuroadaptations).
Analgesic Effects of Drugs of Abuse
As points of interface between the physiology of pain and addiction are considered, it is important to recognize that many classes of abused drugs have analgesic properties, particularly opioids, sedative–hypnotics (particularly benzodiazepines), and alcohol at high doses.
General Effects of Addiction on Pain
Drug addiction can affect nociceptive input, processing, and/or modulation in several different ways, including influencing sympathetic arousal and negative mood states via the direct effects of drugs and the subsequent effect on reward-relevant systems. Further, a strong and persistent negative affective state accompanies withdrawal from many drugs of abuse, which can augment the subjective discomfort associated with pain. Finally, the interpersonal conflicts, role adjustments, and social support losses that accompany addiction can worsen the experience of pain, while a chaotic and drug-oriented lifestyle makes it difficult to comply with regimens.
Potential Neurobiologic Basis for Overlap of the Allostatic States of Addiction and Pain
Links have been hypothesized to exist between the neural mechanisms responsible for a hypersensitive negative emotional state (termed “hyperkatifeia”) and opioid-induced hyperalgesia (OIH) or maldynia. The spino(trigemino)–ponto–amygdaloid pathway, which projects from the dorsal horn of the spinal cord to the mesencephalic parabrachial area and then to the central nucleus of the amygdala, has been implicated in processing emotional components of pain perception. Pain-responsive neurons are also abundant in the lateral part of the central nucleus of the amygdala, an area that also may be responsible for negative emotional responses to abused drugs.
Unique Effects of Opioid Addiction on Pain
The effects of addictive disease on pain become pertinent when treating individuals addicted to opioid drugs, because the class of drug abused also is the primary pharmacologic tool for the treatment of clinical pain. Opioid addiction and opioid analgesia are dependent upon opioid agonist activity at the mu opioid receptor. Since the same receptor is central to both addiction and pain systems, it is reasonable to expect that perturbations in the latter might be evident in individuals chronically exposed to opioids (agonists or antagonists) in the context of the former.
Pain and Methadone Maintenance Patients
Studies have found that methadone-maintained individuals reliably demonstrate poor tolerance for experimental pain. These patients not only receive analgesic effect from daily, high-dose methadone but present a case for the antianalgesic (hyperalgesic) effects of chronic methadone therapy.
Withdrawal Hyperalgesia
Hyperalgesia and spontaneous muscle and bone pain are cardinal symptoms of opioid withdrawal. OIH exists independent of the withdrawal syndrome and can exist in the presence of opioid analgesia. The mu opioid receptor has been shown to have a key role in the development of hyperalgesia. We now understand a biphasic response to opioid administration, in which analgesia is an early response followed by the longer-lasting hyperalgesic state. Studies have also shown that opioid-addicted individuals with poor pain tolerance may suffer a more severe form of addiction, have difficulty tolerating the discomfort (pain) inherent in detoxification and early abstinence, and be more likely to relapse.
OIH and Tolerance
Analgesic tolerance has long been an untested concern for withholding opioids in the treatment of chronic pain. This concept may require reconceptualizing in order to determine the utility of chronic opioid therapy for this patient population.
Mechanisms of OIH
Various physiologic explanations for the development of OIH have been offered, focusing on both spinal and supraspinal systems. Some studies have shown potential utility of NMDA receptor and neurokinin-1 receptor antagonists for the treatment of OIH.
Clinical Evidence of OIH
Probably the best described evidence for OIH in humans is found in postoperative patients, who received opioids intraoperatively, likely in a dose-dependent manner. It is theorized that opioid exposure during surgery-induced hyperalgesic changes resulting in increased pain and opioid need in the postoperative period. Reports of OIH in patients with chronic pain are much less common and are primarily limited to individuals with malignant pain.
Genetic Factors Underlying Pain and Addiction
Individual differences in pain tolerance and opioid response may potentially be affected by genetic factors. For example, heritable differences in hepatic P450 isoenzyme activity affect both the amount of reward and analgesia received from an opioid.
Genetics of Pain and Addiction
Genetics has focused on polymorphisms in the mu opioid gene receptor (OPRM) with regard to pain sensitivity, opioid analgesic response, and addiction. Probably best characterized is the single nucleotide polymorphism A118G of the OPRM, with variant allele-carrying individuals requiring about double plasma levels of morphine. Genetic differences in response to opioids influence the propensity to develop OIH.
KEY POINTS
1. There are two basic types of pain: chronic nociceptive pain and chronic neuropathic pain.
2. A number of biopsychosocial factors influence the neuroplastic changes in the CNS that determine an individual’s experience of pain.
3. Pain can be characterized as three major “stages,” including (1) nociception, (2) persistent and/or repeated nociception, and (3) the consequences of neurologic damage.
4. Emotional states can increase acute pain and reactivate or worsen chronic pain. The amygdala plays a key role in this regulation of emotional responses to pain.
5. The clinical interaction of pain and addiction is particularly complex in the case of addiction to opioids, as these drugs appear to be imbued with both analgesic and hyperalgesic properties. Further, accumulating genetic data suggest that pain, opioid analgesia, and opioid addiction may share similar patterns of gene expression.
REVIEW QUESTIONS
1. Development of chronic neuropathic pain as opposed to chronic nociceptive pain involves all the mechanisms described below except:
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