Status Report on Role of Stimulants in Chronic Pain Management
Stimulants are a class of compounds that have a sympathomimetic or uplighting action on the central nervous system (CNS). Internal or endogenous stimulants are known as catecholamines because a portion of the molecule is catechol. The best known examples are dopamine, norepinephrine, and epinephrine. The latter terms also are called adrenaline and noradrenaline, so their stimulant action on the body is often called “adrenergic.”1
Regardless of terminology, stimulant or catecholaminergic compounds have an expanding role in pain management for a number of reasons. They have been shown to have innate analgesic properties, in addition to potentiating opioids, enhancing some mental and physiologic functions, and treating some common comorbidities of chronic pain, including fatigue, depression, daytime sedation, obesity, and attention deficit hyperactivity disorder (ADHD).2-7
Some recent basic science research will accelerate this expanded role.8-10 Consequently, Practical Pain Management brings to you this status report on stimulants.
Recent Compelling Studies
Recent studies provide a compelling scientific basis for the increased use of stimulant compounds in chronic pain management. Collectively, these studies quite convincingly show that stimulants may be necessary for chronic pain control. In one study, Taylor et al found that inflamed microglia in chronic pain states do not adequately release and activate dopamine in the CNS, which is necessary for pain control.8 They wrote: “Our findings demonstrate that a peripheral nerve injury activated microglia within reward circuitry that result in disruption of dopaminergic signaling and reward behavior. These results have broad implications that are not restricted to the problem of pain, but are also relevant to affective disorders associated with disruption of reward circuitry. Because chronic pain causes glial activation in areas of the CNS important for mood and affect, our findings may translate to other disorders, including anxiety and depression, that demonstrate high comorbidity with chronic pain.”8
In another study, Parent et al found low plasma norepinephrine and metanephrine concentrations in patients with chronic pain.9 “Our results clearly show a deficit in pain inhibition, along with lower plasma norepinephrine and metanephrine concentrations in chronic pain subjects, compared to pain-free subjects. No differences were found in cerebrospinal fluid neurotransmitter concentrations,”they noted.9 This complements a prior study that found low plasma norepinephrine in patients with diabetes with polyneuropathy.11
Other relevant research shows that descending neural pathways from the brain to the periphery generate a great deal of chronic pain.1,10,12 Catecholamines play a critical role in the inhibition of descending pain signals.1,10,12 Now, we have studies that document that patients with chronic pain have plasma catecholamine levels that are low and may be inadequate to inhibit descending pain signals. Taken together, these recent studies tell us we likely will need externally administered stimulants to substitute for lack of central cathecholaminergic activity and to make up for a peripheral, plasma catecholamine deficiency to control descending pain signals.
Reluctance to Use Stimulants
Given the historical effective use of stimulants in severe pain and the recent scientific evidence that catecholamine compounds are necessary for pain control, it is clear that the use of stimulants should be expanded. Physicians have been reluctant, however, to prescribe stimulants to pain patients for fear of abuse or addiction and concerns that high blood pressure and tachycardia may result.
At this time, there are no reports documenting abuse, diversion, or addiction with stimulants in patients with legitimate chronic pain. However, there are numerous reports of misuse and abuse of stimulants in patients with other conditions, especially among those being treated for ADHD. In a review on abuse of medication in patients with ADHD, Clemow and Walker wrote: “Regionally-specific, stimulant-induced elevations in brain dopamine appear to be integral to both efficacy in ADHD and potential for abuse. Overall, the data suggest that ADHD medication misuse and diversion are .... with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.”13
To minimize risk, certain measures are recommended. One is to use an off-label consent form when prescribing stimulants, which lays out the risks of dependence, hypertension, and tachycardia. As when prescribing opioids, regular clinic visits and monitoring for aberrant behavior involving stimulants should be done. Periodic urine and/or blood testing can be requested because stimulants now are a component of test profiles.
The risk for hypertension and tachycardia is widely overstated. Although stimulants may cause hypertension and tachycardia in patients without pain conditions, these adverse effects (AEs) rarely occur in chronic pain patients. In fact, there may be a counterintuitive, physiologic effect of stimulants in chronic pain patients.14 In my experience, stimulants usually lower blood pressure and pulse rates in chronic pain patients. Also, pain patients rarely, if ever, report euphoria with stimulants.
The reason for this counterintuitive effect in chronic pain patients is somewhat unclear, but it is likely related to the oversensitization of the nervous system in chronic pain states and the deficiencies of central and peripheral catecholamines. Practitioners obviously should monitor chronic pain patients for elevated blood pressure and pulse rates, but a reduction, not an elevation, in these physiologic measures is the usual finding in this population. Although there are obvious risks to stimulant treatment of chronic pain patients, the long positive history of their use, the absence of reported AEs and abuse in pain patients, and the need to treat certain comorbidities, make it clear that the benefits of stimulant treatment outweigh its risks.
History of Stimulant Discovery
Given the emerging and expanding use of stimulants in pain management, it is most desirable that pain practitioners have some familiarity with the history of stimulant use in pain treatment, so that all concerned parties know that this is not some new, radical development.
More than a century ago, in 1904, Weber showed that catecholamines would relieve pain when he applied epinephrine (adrenaline) to exposed spinal cords of cats.15 Even prior to this date, in 1896, the renowned British physician Herbert Snow recommended a mixture of morphine and cocaine for patients suffering from advanced disease.16 The original and infamous “Brompton Cocktail” was invented in the 1920s at the Royal Brompton Hospital, in London. The cocktail consisted of morphine or diacetylmorphine (heroin), cocaine, ethyl alcohol, and chlorpromazine for nausea. This cocktail usually was reserved for terminally ill patients with cancer or tuberculosis.