Pain and addiction

This chapter will focus on two important topics: the basic science of substance use disorders (SUDs) from a neurobiologic perspective and how to apply this to the clinical assessment and management of the high‐risk patient.

This is hardly a complete exploration of the subject but should give the reader a practical approach to the clinical care of this challenging population of patients. It is the authors’ sincere hope that all pain practitioners will become talented amateurs in the field of addiction medicine [1].

Neurobiology of addiction

Addiction is a treatable chronic neurobiological disease influenced by genetic, psychosocial and environmental factors. It involves brain centers that normally mediate arousal and reward in situations that enhance the growth and survival of the person, such as food, sex, social interactions and unexpected novel stimuli. Prescribed opioids and drugs of abuse activate these circuits to a much greater extent and without reaching satiety compared to normal stimuli. They tend to serve the individual no useful purpose.

Exciting advances in neuroscience and functional imaging research are beginning to clarify the pathophysiology of addiction as developing through a framework of three recurring stages: binge and intoxication; withdrawal and negative affect; and preoccupation and anticipation (or craving) [2]. Each stage involves activation of specific neural pathways with behavioral correlates which worsen with repeated exposure to a reinforcing substance as neuroplastic changes occur to brain systems that mediate reward, stress and executive function. These behavioral manifestations form the basis of the diagnosis of a SUD with hallmarks of continued use of a substance despite harm, impaired control over use, compulsive use and cravings [3].

In the initial stage [2], the substance (or prescribed medication) will cause release of dopamine and other neurotransmitters (endorphins, serotonin, GABA, acetylcholine) into the ventral striatum. This results in the subjective experience of reward or a “high” (or relief of pain in patients with a chronic pain condition), that positively reinforces their use.

At the same time, normally countervailing circuits maintain proper inhibition and decision making, motivation, stress reactivity and awareness of inner body states. These “braking” circuits become less effective with ongoing use of the drug – there is no satiety as with normal stimuli like food or sex.

Over time, less dopamine is released with repeated exposure to the drug itself, but more in anticipation of the reward, a process known as conditioned reinforcement [4]. A previously neutral stimulus (e.g. a pharmacy) becomes more rewarding through its association with the drug and becomes a reinforcer in its own right.

This “cuing” is a normal evolutionary adaptation meant to provide us more triggers to engage in rewarding/adaptive behaviors and involves the same molecular mechanisms underpinning learning and memory via synapse formation. For example, we feel a sense of wellbeing not just at the thought of our favourite meal, but when we think of where and with whom we ate that meal.

The withdrawal and negative affect stages [5] occurs when drug use is stopped or precipitously reduced. The symptoms vary depending on the substance used and the extent of use and are thought to result from two processes: reduced activation of the reward circuitry and activation of the stress of “anti‐reward” systems in the greater amygdala.

Tolerance [6]

Tolerance is defined by either of the following:

1. a need for markedly increased amounts of a substance to achieve intoxication or a desired effect.
   
2. markedly diminished effect with continuous use of the same amount of a substance.

The important point here is that tolerance is an expected, neuroadaptive response to chronic agonist exposure. Whether this is good or bad depends on perspective. Tolerance to the cognitive impairment associated with opioids occurs relatively quickly and is considered a good thing; tolerance to the analgesic effects of an opioid is generally considered a bad thing. In a similar fashion, a person can lose tolerance, especially to the respiratory depressant effects of this class of drug, relatively quickly, increasing the risk of overdose and death, substantially [7].

Physical dependence/withdrawal

For the most part, physical dependency is an expected consequence of exposure to many agonist agents, including the opioid class of drugs. It is characterized as a “class‐specific constellation of symptoms associated with abrupt discontinuation of a drug, rapid reduction in drug levels, or administration of an antagonist” [8].

It is important to remember; withdrawal symptoms are typically the opposite of the therapeutic effect. As an example, sedatives that depress the reticular activating system lead to hyperactivity in that system upon withdrawal. In some cases, seizures may be the result. In the case of the opioid class of drugs, their primary sympatholytic effect leads to sympathetic over activity with multiple resulting symptoms (Table 39.1). As such, one of the common classes of non‐opioid agents used to treat opioid withdrawal are the alpha‐2‐agonists such as clonidine. Their ability to mitigate symptoms of opioid withdrawal is only partial; opioid tapering, with or without substitution remains the gold standard for the acute management of opioid withdrawal.

Interestingly, through the phenomenon of cross tolerance, the symptoms of withdrawal can be reversed or mitigated by the reintroduction of the original drug or a drug of a similar class [8].

As a rule, the more potent, shorter acting agents have a more intense withdrawal syndrome than other, less potent or longer acting agents. It is important to note that withdrawal is less about drug levels than it is about rate of change of drug levels in the physically dependent user.

For example, if a methadone maintenance patient has a peak to trough ratio of 2, 50% of the peak drug level remains prior to administration of the next dose, assuming a “once daily” dosing regimen commonly seen in maintenance treatment.¹ Most patients are quite stable on once‐daily dosing, even though the serum level of drug has been reduced by 50%.

Contrast this with an individual who is given an injection of the antagonist, naloxone. In this case, the abrupt reduction in μ agonist effect is generally very poorly tolerated. Unfortunately, individual response to serum levels of drugs is highly variable: generally, the longer the person is on the drug, and the higher the dose, the more severe are the withdrawal symptoms.

In fact, some people on relatively low doses of opioids may experience severe withdrawal; others on much higher doses seem relatively unaffected by relatively large dose reductions. As such, withdrawal symptoms should not be considered a reliable indicator of treatment compliance, even in patients on relatively large doses of medication.

It is also useful to look at opioid withdrawal in terms of early, “subjective” effects and late, “objective” effects. The early, subjective effects include a dysphoric state. The objective signs of withdrawal are typically more intense. For a more complete examination of opioid withdrawal assessment, the reader should review the original paper by Handelsman et al. [9].

With ongoing drug use, less dopamine is released and functional neuroimaging reveals reduced expression of dopamine D2 receptors in the reward circuits, especially in addicted individuals [10]. Both of these phenomena contribute to a reduced responsiveness of the reward system. As a result, normal adaptive behaviors become neglected in favor of the much more rewarding substance [11].

Activation of the “antireward” system in the amygdala also occurs at this stage [12]. Corticotropin‐releasing factor (CRF), dynorphin, endocannabinoids and other neurotransmitters become over‐expressed, promoting stress reactivity and intense dysphoria. Instead of experiencing the intense reward (i.e euphoria or pain relief) when they took the drug in the first stage, patients at this point will obtain diminishing reward over time and instead experience relief from an overwhelmingly negative experience. The quickest way for them to feel “normal” is to take more drug, an intensely powerful negative reinforcer. It is in this stage that patients act as if getting the drug is key to survival and will do “whatever it takes” to escape withdrawal and dysphoria. Thus, the subject is no longer using to get high but rather to feel once again normal. This concept is somewhat paradoxical and difficult to process for many clinicians unfamiliar with SUDs

In those with persistent pain, a parallel neuroplastic process amplifies the negative affect. The brain networks involved with pain shift central processing of pain away from sensory and towards emotional and cognitive brain areas, the same areas being disrupted by anti‐reward activation [13]. Seeking pain relief from prescribed opioids AND the elimination of abstinence or withdrawal symptoms (between doses of the prescribed opioids) become strong conditioned reinforcers, as does everything along the way to obtaining that relief [14].

The preoccupation and anticipation stage occurs when a person may seek substances after a period of abstinence and becomes preoccupied with using again (i.e. craving). It is characterised by disruption of executive functions in the prefrontal cortex (PFC), such as self‐regulation, decision making and importantly exercises control over incentive salience, a cognitive process that confers desire and motivation to cues associated with stimuli. Many neuroscientists understand the function of the PFC as a balance between a “Go” system and a “Stop” system [11]. The upregulation of the Go system by the increased activity of glutamate increases cravings and habits associated with substance use, while the downregulated Stop circuits lead to more impulsivity and compulsive drug seeking and less dampening of the stress circuits.

The power of drugs of abuse, including pain medications, to produce feelings of wellbeing and relief from negative feelings (and/or pain) can foster the emergence of compulsive use. The development of addiction requires not only repeated or ongoing exposure to a medication or substance that is potentially addicting, but also must occur in an individual with certain biological, psychological, genetic and sociological susceptibilities. With increased salience (binge/intoxication stage), combined with reduced reward and increased stress sensitivity (withdrawal/negative affect stage) and impaired executive function, a perfect storm of neuroplasticity can result in drug seeking and use especially in those at risk and can become overpowering.

One should understand the difference between addiction and physical dependence. The latter is a normal, expected neurophysiological adaptation that occurs with chronic exposure to certain classes of substances, and is manifest by a withdrawal syndrome specific to a class of medication or substance which is abruptly discontinued or reduced. Physical dependence is neither necessary nor sufficient in the diagnosis of an addiction [15], and, in fact, is mediated by different neural pathways than those involved with addiction [8, 16].

The application of our understanding of the neurobiology of addiction to the problematic use of prescribed medications for the legitimate treatment of chronic pain remains a point of constant debate. However, taking a consistent approach to assessing these susceptibilities in all patients before embarking on treatment and all through their trajectory of care will result in less risk and significantly improved outcomes (Figure 39.1).

Approach to clinical care in the physically dependent/substance use disordered pain patient

In recent years, clinical approaches to the chronic use of the opioid class of drugs in the management of pain has fallen out of favor. The early use of opioids, in often excessively high doses has been replaced by a much more cautious and sadly, not always rational use of these potent drugs[17]. Pharmacologic principles such as “full μ agonists have no ceiling” were interpreted as meaning “no limit to clinical dosing”, leading to excessive use of medication by some patients with chronic pain. Of course, this pharmacologic principle must always be offset by a careful risk/benefit analysis. Once again, the pendulum has swung from the liberal use of opioids to a much more constrained view of these medications.

As a result, sometimes onerous restrictions have been placed on these opioids, resulting in many legitimate patients with pain, often the more marginalized ones, being subjected to forced dose reductions and, in some cases, “tapers to discontinuation.” Unfortunately, this has led some patients to depart from traditional medical sources of these drugs, instead turning to non‐medical sources of drugs. Many of these are counterfeit, often laced with high potency opioids such as fentanyl or even carfentanyl, with tragic results.

In this sense, there most certainly is a prescription opioid problem in North America. Unlike previous years where the use was almost ad lib, excessive restrictions are now leading established medical users to find their previously prescribed opioid drugs being supplied by illegitimate sources. In doing so, the illegal drug trade in counterfeit pharmaceuticals blossomed, leaving a trail of despair and death in their wakes [18, 19].

From the previous section on addiction medicine, there is an undeniable but complex difference between simple physical dependency and the complex disease of addiction. This difference becomes more challenging when the agent of misuse is prescribed legally by a medical professional [20].

Ballantyne et al opined that the terms opioid dependence and addiction might essentially be “a distinction without a difference”[21]

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