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14 Articles in Volume 15, Issue #6
Antihistamine for G-CSF–Induced Bone Pain
Book Review: Advanced Headache Therapy
Brain Drain: Lymphatic Drainage System Discovered in the Brain
Case History of Chronic Migraine: Update 2015 Part 2
Disturbed Sleep: Causes and Treatments
Is Topical Ketamine Ready For Prime Time?
Letters to the Editor: Central Sensitization, Microglia Modulators, Supplements
New App Helps Interpret Urine Drug Test Results
Osteoarthritis Update: 2015
Pain Catastrophizing: What Clinicians Need to Know
PPM Editorial Board: Tips for Treating Osteoarthritis
Practical Overview of Osteoarthritis
Status Report on Role of Stimulants in Chronic Pain Management
Treatment of Osteoarthritis

Status Report on Role of Stimulants in Chronic Pain Management

Stimulant administration in chronic pain patients may increase analgesia, improve mental and physical functions, and treat the comorbidities of fatigue, depression, daytime sedation, obesity, and attention deficit hyperactivity disorder (ADHD).

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.

Cardiovascular Risks

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.

Dextroamphetamine and morphine were found to be an excellent combination for pain relief during World War II.17 Also, during the wartime period, it was found that stimulants would counteract the respiratory depression and sedation of opioids.18,19 Although the use of this combination was known, it was seldom used clinically and was essentially unreported in the medical literature for several years after the war.

Instead, researchers, commercial producers, and practitioners turned their attention to combining stimulants, including caffeine, into single commercial products because stimulants clearly potentiated opioids and aspirin.20,21 This led to the development of popular combination drugs consisting of weak stimulants with opioids and/or anti-inflammatory agents. The combination products of codeine with aspirin or acetaminophen and caffeine are widely known and have been highly prescribed for over 2 generations.21

Although not yet widely adopted, a number of excellent studies on stimulants and opioids in combination were done between 1950 and the end of the last century.22-29 All of these studies, whether done in animals or humans, showed remarkable enhancement of pain relief when stimulants were combined with opioids. One of the surprising and positive findings in these studies was that stimulants not only gave better pain relief, but subjects (animals and humans) routinely performed mentally and physically better and had less respiratory depression and sedation than with opioids alone.3-5,29

In 1977, I conducted a randomized, controlled trial of dextroamphetamine with morphine in post-operative patients and clearly documented the superior pain-relieving effects of the simultaneous use of both agents.30 As noted above, studies in recent years have shown that catecholamines are necessary to control the descending pain pathways from the brain to the periphery. All told, the history and research of stimulant use in chronic pain states is compelling.

Analgesia and Opioid Sparing

It is clear that stimulants possess, in themselves, analgesic properties. The historical belief that they simply potentiate opioids may be too simplistic. They increase the analgesic properties of non-opioids and provide pain relief independent of the endogenous opioid system and externally administered opioids.6,31 Norepinephrine appears to be the major catecholamine that controls pain.1,7 This explains why pure dopaminergic compounds, such as L-Dopa and amantadine, have not found a place in pain treatment. In the author’s experience, stimulants may spare opioids in many chronic pain patients.14 Some patients even claim that stimulants may provide equal pain relief to opioids.

Treatment of Comorbidities

As noted, in addition to analgesia, stimulants treat or control some of the comorbidities commonly found in chronic pain patients: fatigue, depression, obesity, daytime sedation, and ADHD (Table 1). At least one of these comorbidities likely will be found in most severe, chronic pain patients. Fortunately, most commercially available stimulants are FDA-approved for treatment of one or more of the common chronic pain comorbidities (Table 2).

Obesity is rampant among chronic pain patients due to multiple factors including immobility, diet, hormone abnormalities, and drugs such as opioids and benzodiazepines that slow metabolism. The weight-control stimulants, phentermine (Adipex-P, others) and phendimetrazine (Bontril, others), are well tolerated by pain patients. Phentermine was marketed with fenfluramine as a combination weight loss product under the name Fen-Phen. In 1997, fenfluramine and dexfenfluramine were voluntarily taken off the market at the request of the FDA after 24 cases of heart valve disease in Fen-Phen users were reported. Phentermine has remained on the market as a Schedule IV controlled substance. Phendimetrazine, a Schedule III controlled substance, functions as a prodrug to phenmetrazine, which was withdrawn from the market due to abuse and misuse. The author has not observed great dependence or addiction with these current agents.32

Daytime sedation in chronic pain patients may have multiple causative factors, including night-time insomnia, hormonal abnormalities, and sedating analgesics, such as long-acting opioids. The stimulant for narcolepsy, modafinil (Provigil), can be effective in some of these patients.

A common but little addressed problem in chronic pain patients is ADHD. Almost universally, severe, centralized, chronic pain disrupts normal neuronal function in the CNS. Patients and their families often are distraught over the pain patient’s inability to concentrate, focus, read, and remember. The stimulants methylphenidate (Ritalin, Concerta, others), dextroamphetamine (Dexedrine, others), and combinations of amphetamine and dextroamphetamine (Adderall, others) are well tolerated by pain patients. Table 3 provides a checklist to aid in identifying pain patients with ADHD. Although this patient checklist has been neither validated nor quantified, it includes various behaviors that typify ADHD in adult pain patients. I consider 3 or more positive answers to likely represent the presence of some attention deficit.

Selection of Stimulant

There are many factors that go into selecting a stimulant. These include cost, health plan coverage, prior exposure to a stimulant, and abuse history. As a general measure, it is recommended that the stimulant selected be for a comorbidity for which the stimulant has a labeled indication. For example, phentermine for obesity and methylphenidate or dextroamphetamine for ADHD.

The initial dosage should be low. A therapeutic principle in pain management pharmacotherapy is to “start low and go slow.” Chronic, centralized pain patients have a sensitized nervous system and many autoimmune characteristics. Consequently, AEs often occur. The dosage of a stimulant should be titrated upward over time to control a comorbidity, enhance pain relief, and potentiate opioids and minimize their use.


A long history of stimulant use for analgesia and recent clinical studies provide a sound rationale for their expanded use in chronic pain management. Catecholaminergic enhancement may be required for CNS activity and inhibition of the descending pain pathways that traverse from the brain down the spinal cord and autonomic nervous system into the periphery. To date, stimulants with catecholamine properties have not been widely used in chronic pain management for fear of abuse and complications such as hypertension and tachycardia. Accumulating evidence clearly indicates, however, that stimulants may be used in chronic pain states to achieve effective analgesia and to treat the common comorbidities of fatigue, depression, daytime sedation, obesity, and ADHD. With regular clinic monitoring, the benefits of stimulants outweigh the risks, and these agents should be more widely used in chronic pain management. The benefits of stimulant administration include enhanced analgesia, improved physical and mental function, reduced opioid use, and treatment of comorbidities.

Last updated on: August 11, 2015
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