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Chronic pain can be nociceptive, neuropathic, or a mixture of both (Exhibit 1-3). Pains such as migraine and fibromyalgia, in which there
is no noxious stimulus and no apparent neuro
logical lesion, are attributed to dysfunction of a structurally intact CNS.
Chronic pain often results from a process of neural sensitization following injury or illness in which thresholds are lowered, responses are amplified (hyperalgesia), normally non-nox ious stimulation becomes painful (allodynia), and spontaneous neural discharges occur. Increased signaling disconnected from noci ceptive input can become autonomous, self- sustaining, and progressive, leading to the con tinuous perception of pain even in the absence of ongoing tissue damage. Thus, chronic pain
is not equivalent to prolonged acute pain and for clinical purposes is best considered a dis tinct disorder (Brookoff, 2005).
The etiology of the abnormal processing in chronic pain is not fully understood. However, there are two main, nonexclusive causes. First,
tissue damage can trigger the release of chem icals that sensitize the nerve fibers and alter gene expression, causing changes in signaling through many different mechanisms. Some
of these changes enable non-pain-conducting fibers to trigger pain in the CNS. Second, pain can result from injured nerve fibers that
regenerate in a neuroma, which generates pain signals with little or no stimulation.
When injury occurs to key pain-processing sectors of the CNS (e.g., the dorsal horn, thalamus), neural signals that pass through them may be interpreted as pain. Injury may also lead to degeneration of pain inhibitory cells. Modulation of nociceptive stimuli and inhibitory responses can occur at one or more locations in the CNS: the peripheral nerves, spinal cord neurons and tracts, thalamus, and cortex (Compton & Gebhart, 2003). Accurate identification of the source of the chronic
pain, and of the neurological processes that modulate it, can lead to rational therapeutic approaches that target the source of aberrant signaling on the CNS pathway.
exhibit 1-3 pain Types
pain’s effect on health
Persistent pain can have significant adverse effects on health. When pain stimuli continu ously trigger the stress response, the acute signs of sympathetic activation (e.g., rapid heart rate, sweating) may cease or appear intermittently, yet the body continues to be stressed. This situation contributes to a sense of exhaustion.
Continued pain can trigger emotional responses, including sleeplessness, anxiety, and depressive symptoms, which in turn produce more pain. Such feedback cycles may continue to cause pain after the physiological causes have been addressed. Several studies show that the out come of pain treatment is worse in the pres ence of depression, or when depression does not respond to treatment, and that the future course of pain syndromes can be, in part, pre dicted by emotional status. The physiological and psychological sequelae of CNCP can be exacerbated by such factors as inactivity and overuse of sedating drugs. Physical inactivity and a lack of engagement with life may also lead to increased levels of anxiety, depression, and an increased risk for suicidal ideation;
these increases may lead a person to use sub stances in an attempt to treat these sequelae of CNCP and the losses that occur due to its presence.
neurobiology of Addiction
A person may use substances initially for several reasons, such as to experience the euphoric effects, to relieve stress, to overcome anxiety or depression (or both), or to blunt the pain (National Institute on Drug Abuse
[NIDA], 2007). With repeated exposure, how ever, substance use in some people can become uncontrollable. The defining characteristics of the disease of addiction have been summarized as the “3Cs” (see the definition of addiction). Changes to the brain occur in a process that is mediated by both genetic and environmental
factors, which result in an overvaluation of the substance, a devaluation of other things, and impaired control of substance-related behavior. Evidence indicates that addiction is a chronic disease.
The primary rewarding effects of addictive substances occur in the cortico-mesolimbic dopamine systems, where several structures link to control the basic emotions and con nect them to memories, which drive behavior. These systems produce sensations of pleasure in response to actions that support survival (e.g., eating, sex) and sensations of fear in response to potential dangers. In a cascading effect, these sensations trigger the endocrine and autonomic nervous systems, stimulating bodily responses. The prefrontal cortex also plays a role in the formation of addictions, modifying pleasure and pain signals based on other considerations. Thus, the brain’s reward and stress systems reinforce life-sustaining behaviors.
Feelings of reward emerge from the core of the limbic system after neurons in the ventral tegmental area (VTA) release the neurotrans mitter dopamine into the nucleus accumbens (NAc). Neural activity within this VTA–NAc circuit is necessary to experience reward, but other areas within the broader brain reward circuit also exert a strong influence. For exam ple, the hippocampus contributes information from the past that may be relevant to the current experience. The amygdala adds critical information about the emotional valence of
the stimulus that activated the reward circuit, thus contributing to the overall motivational power of the experience. In addition, parts of the prefrontal cortex (i.e., anterior cingulate and orbitofrontal cortices) help integrate all the information, a vital function that allows the individual to decide whether to initiate
or suppress a particular behavior in response to the stimulus.
Managing Chronic Pain in Adults With or in Recovery From Substance Use Disorders
Most addictive substances increase the levels of dopamine in limbic targets well beyond what occurs in naturally rewarding situations (e.g., sex, food). Some drugs (e.g., marijuana, heroin) produce dopaminergic effects indi rectly. Amphetamines cause the release of dopamine, and cocaine prevents its reuptake; both effects result in amplified messaging that eventually disrupts normal neuronal signaling.
It appears that the brain adjusts to excess dopamine levels by producing less dopamine and by reducing the number of receptors that respond to it in the receiving (postsynaptic) neuron. As a result, the pleasurable effects of
a drug become diminished with continued use. The pleasurable effects of normal activities also are blunted, creating a state called anhedonia (an inability to experience pleasure).
It is commonly believed that continued substance use is driven by the need to prevent symptoms of withdrawal; however, this idea is misleading. Withdrawal, as commonly conceptualized, involves rebound symptoms resulting from the drug’s absence. In the
case of opioids, these symptoms include, but are not limited to, anxiety, sweating, tachycardia, diarrhea, piloerection, and chills. Although unpleasant, these symptoms are typically absent after a relatively brief period of detoxification or weaning and do not explain phenomena such as addiction relapse and prolonged craving. Even though detoxi fication is quick and technically easy, the prevention of relapse is extremely difficult and, in fact, the majority of those who attain abstinence experience at least one relapse (Dennis, Foss, & Scott, 2007). These more difficult problems are thought to result from the prolonged impairment of hedonic tone
and conditioned responses that lead to intense craving.
The dysregulation of the brain’s reward system that occurs through substance use is paralleled by similar dysregulating effects in the stress system. Use of an addictive substance increases the flow of neurochemicals (e.g., corticotropin releasing factor, norepinephrine, dynorphin). These chemicals can produce a negative emotional state that manifests as chronic irri tability, emotional pain, lethargy, disinterest in natural rewards, and other dysphoric condi tions. The stress response becomes more sensi tive with repeated withdrawal and can persist into abstinence (Koob, 2009).
An individual may seek to avert the stress response by again using the substance. This negative reinforcement combines with the positive reinforcement of the substance’s euphoric effects in an operant process that creates a compulsion for substance use. Thus, addiction is reflected in compulsive use combined with loss of control mediated by memory (cue-induced triggers for reuse), substance-induced reductions in executive
functioning that hamper rational decisionmak
ing, and habit formation (Koob, 2009).
risk Factors for Addiction
People who use substances with addictive potential may develop tolerance to some of their effects and develop some degree of physi cal dependence. However, only a minority develops the disease of addiction. Important risk factors for addiction include genetics, psychological factors, and environmental factors.
Genetics plays a substantial role in risk factors for addiction: NIDA (2007) estimates that between 40 and 60 percent of a person’s vul nerability to addiction may be genetic. The
disease of addiction may be more heritable
than type 2 diabetes, hypertension, and breast cancer (Nestler, 2005). Genes also underlie human variability in drug metabolism, suscep tibility to psychiatric disorders that commonly co-occur with addiction, and response to envi ronmental risk factors (e.g., drug availability, peer group pressure [Vaillant, 2003]).
Mental illness is another major risk factor for addiction (Volkow & Li, 2009), and the two conditions have high comorbidity (NIDA,
2009). One condition can follow the other (NIDA, 2007). For example, a person may attempt to relieve depression or anxiety with substances, and this behavior may lead to addiction. Conversely, chronic substance use may lead to mental disorders, such as psy chosis, or make existing mental illness worse (NIDA, 2007). Environmental influences on addiction include, but are not limited to, pov erty, poor parental support, living in a com munity with high drug availability, and using substances at an early age (NIDA, 2007, 2009; Volkow & Li, 2009).
Addiction to one substance can be linked with addiction to other substances in a pattern termed cross-addiction. An individual who vol untarily or involuntarily decreases use of one substance may increase use of another sub stance with similar effects on the brain (e.g., the person with an alcohol use disorder may use barbiturates for the sedative effects). The term cross-addiction is also used to describe simultaneous addiction (e.g., co-occurring addictions to nicotine, alcohol, and marijuana).
Cross-addiction is not official diagnostic nomenclature; rather, it refers to the observa tion that a person with an addiction to one substance may develop addiction to a sub sequent substance, especially if the original drug of choice becomes inaccessible or is
relinquished for other reasons. For example,
a study of patients hospitalized for controlled- release oxycodone addiction found that the majority (77 percent) had previously had a
non-opioid SUD (Potter, Hennessey, Borrow, Greenfield, & Weiss, 2004).
Individuals with chronic pain and histories of SUDs may be at increased risk of cross- addiction to any medication that acts on the brain as a reinforcing agent (Edlund, Sullivan, Steffick, Harris, & Wells, 2007). Because of cross-addiction, persons who abuse marijuana may be at increased risk for opioid addiction. People with alcohol use disorders have been found to be more than 18 times as likely to report nonmedical use of prescription medica tions as people who do not drink (McCabe, Cranford, & Boyd, 2006).
The cycle of chronic pain and
Although multiple factors influence the course of addiction, CNCP provides both positive
and negative reinforcement of substance use. Positive reinforcement occurs when a behavior is followed by a consequence that is desirable— a donkey’s walking may be rewarded by a carrot. Negative reinforcement occurs when
a behavior is followed by the elimination of
a negative consequence—a donkey’s walking may eliminate the blows from a stick. For example, euphoria is a positive reinforcer for taking heroin, and pain reduction is a nega tive reinforcer for taking heroin. Prescribed opioids, benzodiazepines, or other medications may dramatically relieve pain or distress (e.g., depression, anxiety). Unprescribed substances may be used for similar reasons; for example, alcohol may promote relaxation or sleep. Such relief is a strong reinforcement for repeated consumption of the substance.
Unfortunately, analgesic and anxiolytic efficacy may diminish over the course of weeks, months,
Managing Chronic Pain in Adults With or in Recovery From Substance Use Disorders
or years as tolerance develops. This loss of effi
cacy often elicits dose escalation to recapture efficacy. This escalation is rewarded, as the increased dose is initially more effective than the lower dose.
If the drug produces physical dependence, the person may have not only increased pain when the substance is absent, but also withdrawal symptoms (e.g., anxiety, nausea, cramps, insomnia). Withdrawal symptoms may lead to an increase in symptoms of depression and an increase in the potential risk for suicide. All these symptoms are relieved by ingesting more of the drug that caused the dependence. A similar situation may occur if the drug is one that elicits rebound symptoms. For example, ergot relieves migraine, but excessive use leads to rebound headaches that are more persistent and treatment resistant than were the original headaches.
An illusion of benefit produced by reinforcing drugs can create a paradoxical situation in
which long-term use of the substance creates
the very symptoms the person hopes to alleviate. People commonly drink to relax or “cheer up,” yet chronic alcohol abuse leads to depression and anxiety.
In some people, a cycle develops in which pain or distress elicits severe preoccupation with the substance that previously provided relief. This cycle—seeking pain relief, experi encing relief, and then having pain recur—can be very difficult to break, even in the person without an addiction, and the development of addiction markedly exacerbates the difficulty. The propensity to develop this cycle is influ enced by genetic and environmental factors; some people will experience greater degrees
of analgesia than others, and some will have more severe or prolonged abstinence symp toms. Genetic variability in susceptibility to these experiences may explain some cases
of iatrogenic addiction.