Archives of Physical Medicine and Rehabilitation
Volume 89, Issue 3, Supplement 1 , Pages S56-S60, March 2008

Interventions in Chronic Pain Management. 5. Approaches to Medication and Lifestyle in Chronic Pain Syndromes

  • Mitchell K. Freedman, DO

      Affiliations

    • Rothman Institute, Philadelphia, PA
    • Corresponding Author InformationCorrespondence to Mitchell K. Freedman, DO, Rothman Institute, 925 Chestnut St, Philadelphia, PA 19107
    • ,
  • Michael F. Saulino, MD

      Affiliations

    • Moss Rehabilitation, Elkins Park, PA
    • ,
  • E. Anthony Overton, DO

      Affiliations

    • Rothman Institute, Philadelphia, PA
    • ,
  • Michele Y. Holding, MD

      Affiliations

    • The Back Pain Center, Phoenixville, PA
    • ,
  • Ira D. Kornbluth, MD

      Affiliations

    • Spine Medicine and Rehabilitation Therapies, Westminster, MD.

Article Outline

Abstract 

Freedman MK, Saulino MF, Overton EA, Holding MY, Kornbluth ID. Interventions in chronic pain management. 5. Approaches to medication and lifestyle in chronic pain syndromes.

This self-directed learning module first reviews the importance of weight management and smoking cessation in the treatment of axial low back pain and then describes the use of medication in complex regional pain syndrome and trigeminal neuralgia. It is part of the chapter on chronic pain in the Self-Directed Physiatric Education Program for practitioners in physical medicine and rehabilitation. The first objective explores the correlation of tobacco usage and obesity with lower back pain. The second objective reviews the option for medication management in patients with complex regional pain syndromes. The third objective examines the management of trigeminal neuralgia in a patient with multiple sclerosis.

Overall Article Objective

To discuss the importance of addressing obesity and smoking cessation in patients with low back pain and medication usage in trigeminal neuralgia and complex regional pain syndromes.

Key Words: Complex regional pain syndrome, Low back pain, Obesity, Rehabilitation, Smoking cessation, Trigeminal neuralgia

 

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5.1 Clinical Activity: To discuss the importance of weight loss and smoking cessation with a 25-year-old woman who smokes cigarettes, is overweight, and is contemplating a spinal fusion for her axial lower back pain 

THERE HAS BEEN a good deal of speculation that smoking may be a predisposing factor for spinal pain. There are several potential mechanisms. Catecholamine release causes vasoconstriction and superoxide ion formation. Toxic chemicals and byproducts absorbed by the smoker, such as cadmium, nicotine, cyanide, and carbon monoxide, may result in decreased blood flow to the vertebral bodies. Smoking in pigs decreases cellular uptake and metabolic production in the disk. Rabbits exposed to nicotine have decreased collagen and proteoglycan synthesis in the intervertebral disk. Blood viscosity is increased because of the erythrocytosis induced by carboxyhemoglobin, and platelet aggregation is increased with long-term nicotine inhibition of prostaglandin E2 production. Smoking can cause vasoconstriction and atheromatous changes in the vertebral blood vessels, which may result in hypoxia and degeneration. Increased coughing may lead to increased pressure on the spine, and diminished bone mineral content may result in microfractures of the trabeculae of the vertebral bodies.1, 2, 3

The exact nature of the association between tobacco use and back pain is unclear. Scott et al3 found a positive association between back pain and current smoking among adult women and men diagnosed with idiopathic scoliosis and women from the general population but not in men who did not have scoliosis. Smoking increased the frequency of back pain in women, and the duration of back pain lengthened as well.3 Kaila-Kangas et al4 showed that heavy smoking and obesity were predictive of hospitalization for intervertebral disorders. Leboeuf-Yde5 looked at a population of 29,000 twins and concluded that a positive association existed between smoking and lower back pain of longer duration. However, smoking was not believed to be causal, and the investigators concluded that the discontinuation of smoking was unlikely to have a great effect on back pain. There was no difference in back pain in monozygotic twins when a twin who smoked was compared with his/her twin who did not smoke.2 Smoking poses a weak risk factor but is not a cause of lower back pain.5

A correlation also exists between nicotine exposure and nonunion of surgical fusions. Silcox et al6 showed that rabbits that were exposed to nicotine were more likely to have a nonunion after spinal fusion. Another study showed that nonunion rates for smokers are 26.5% versus 14.2% for nonsmokers. Nonunion is thought to be associated with decreased revascularization of the bone graft from exposure to nicotine. Patients who quit smoking for 6 months after the spinal fusion improved to a 17.1% nonunion rate. Vascular effects of nicotine are reversible within 2 weeks of nicotine elimination.1 Optimally, patients should stop smoking between 2 weeks before and 6 months after fusion. Interestingly, smokers who underwent spinal fusion reported less satisfaction with their surgical results than did nonsmokers who had the same surgery.7, 8 Patients who smoke are at risk for perioperative problems including wound complications and adverse cardiopulmonary sequelae. Smoking cessation before surgical intervention may lessen these risks.

In the United States, less than 10% of the 20 million people who quit smoking for a day remain abstinent 1 year later. Annually, only 2% to 3% of smokers are able to permanently quit smoking because of the nicotine, which is highly addictive. Nicotine-replacement medications include nicotine gum, patch, inhaler, nasal spray, and sublingual tablets. Other first-line pharmacologic interventions for smoking cessation include nicotine receptor partial agonists and bupropion. Nicotine-replacement therapy increases the odds of smoking cessation by approximately 2-fold. Counseling, hypnosis, and acupuncture are a few of the nonpharmacologic options.9, 10, 11

Excessive body weight may be a predisposing factor for back pain. Intuitively, one would think that the increase in body mass would put a greater load on the lower back and cause altered body mechanics with daily activities. Leboeuf-Yde et al12 found a modestly positive association between body mass index (BMI) and low back pain that increased with the duration of pain in a study of 29,000 twins. However, in monozygotic twins who were dissimilar in BMI, no link existed between back pain and obesity, and it was concluded that obesity was not causal of back pain. Obesity has definitely been linked to cardiorespiratory disease, diabetes, gallbladder disease, and breast cancer.13 Marcus14 found increased BMI to be associated with depression, comorbid disability, and reduced quality of life for physical function. It could also be hypothesized that obesity may be present in people with poor lifestyle, in those who are sedentary during work and leisure activities, or in persons who have poor postural habits. Mayer et al15 looked at patients with chronic occupational spinal disorders and extended disability (average, 16mo) to see if obesity is a risk factor for poor outcome with an interdisciplinary restoration program. Although obesity is more prevalent in this population, they concluded that obesity did not negatively affect the outcome of the program.15 Because of inactivity, physical deconditioning, and depression, patients with chronic spinal disorders are at higher risk for obesity.16 Medications such as antidepressants and membrane stabilizers also may contribute to weight gain. Although obesity is associated with lower back pain, it has not been proven to be causal.

Weight loss should be pursued with dietary management. An inverse relation exists between physical activity and weight gain. Although physical activity alone does not cause weight loss, it appears that 60 to 90 minutes daily of moderate intensity activity is required to maintain weight reduction.17 Depression should be treated, and medications promoting weight gain should be weaned when possible.

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5.2 Clinical Activity: To consider the ramifications of various medication classes in the treatment of chronic pain (including off-label use of medications) in a 33-year-old patient with chronic regional pain syndrome in the right upper extremity 

As with many neuropathic pain conditions, no medications are specifically approved for chronic regional pain syndrome (CRPS). The 2 neuropathic pain conditions that are most commonly studied during the drug approval process are postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN). Both of these disorders are considerably different from CRPS in pathophysiology, presentation, and clinical course. Extrapolation of applicability from PHN and DPN to CRPS may not be valid. Table 1 outlines the medications that have U.S. Food and Drug Administration (FDA) approval for these neuropathic pain conditions as of October 2006. By definition, all pharmacologic treatment for CRPS will be considered off-label. Practitioners should be aware that a patient’s insurance coverage for medications may be restricted to on-label indications.

Table 1. FDA Approval Status of Medications by Condition
Trade NameGeneric NameCondition
DPNPHN
LyricaPregabalinYesYes
LidodermTopical lidocaine 5% patchNoYes
CymbaltaDuloxetineYesNo
NeurontinGabapentinNoYes

Multiple pharmacologic interventions are available for the treatment of neuropathic pain. The majority of reviews18, 19, 20 that examine treatment strategies promote a rational polypharmacy approach. Although this view is often supported by treatment guidelines, polypharmaceutical regimens have rarely been evaluated in a vigorous manner in the literature. The remainder of this section will examine the common classes of medications used to treat neuropathic pain as isolated agents, recognizing that this methodology may not reflect clinical practice.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have a long history in pain management. The primary indication is for management of acute pain. These agents exert their therapeutic effect by interfering with the inflammatory process through inhibition of the cyclooxygenase (COX) enzyme. Most of the NSAIDs act as nonselective inhibitors of both isoforms of COX (COX-1 and COX-2). Inhibition of this enzyme results in a decreased formation of prostaglandins, which potentiate pain transduction peripherally and pain transmission centrally. The peripheral mechanism of COX inhibition is better understood than the central action. Highly selective COX-2 inhibitors were introduced in the last 10 years with the goal of reducing the gastrointestinal toxicity associated with chronic NSAID use. Two of these COX-2 agents have been removed from the market because of significant cardiovascular and dermatologic events associated with their use.21 Other COX-2 inhibitors are in development. Although potential benefits exist for the chronic use of COX inhibitors, especially with the emerging understanding of their role in central pain transmission, the potential for adverse cardiovascular, renal, and gastrointestinal effects may severely limit their long-term use. These adverse effects are particularly concerning in the patient with vascular disease because NSAIDs will interfere with the antiplatelet effects of aspirin. At this time, it is recommended that aspirin 81mg be taken 30 minutes before taking an NSAID to avoid negating the antiplatelet effect of the aspirin.22 Other gene products of the COX gene (COX-3, COX-1b, COX variant protein) may represent non-COX activity. These alternate gene products may also be amenable to pharmacologic modulation, potentially by known agents such as acetaminophen. As these concepts come to light, it is conceivable that the role of NSAIDs within CRPS treatment will also emerge.23, 24

Topical application of therapeutic agents is another reasonable option. Potential advantages of this strategy include higher local drug concentrations at the site of pain production or transduction, lack of drug interactions, ease of use, minimal dosing titration, and reduced systemic administration. Topical delivery of medication differs from transdermal delivery; topical agents target a site immediately adjacent to the delivery vehicle, whereas transdermal agents use the skin as their delivery system. Capsaicin, a natural constituent of chili peppers, exerts its effect selectively on small-diameter sensory neurons. The drug has shown efficacy in a number of painful conditions including PHN, DPN, trigeminal neuralgia, and osteoarthritis. Although it has shown benefit, it is rarely considered effective in monotherapy and is typically used as an adjunctive agent. Limitations of capsaicin include burning pain at the site of administration and therapeutic lag in pain reduction. Local anesthetics block voltage-gated sodium channels. These ion channels play a major role in peripheral ectopic neuronal discharges that occur in chronic neuropathic pain. Although local anesthetics have been used to abolish nerve conduction, they can also be used at lower concentrations to block spontaneous and evoked activity without affecting impulse propagation. Thus, topical lidocaine in the form of a gel or patch can be used for chronic neuropathic pain. This agent should be applied to the area where ectopic discharge potentially forms. Several other agents are amenable to topical administration. These agents include NSAIDs (particularly diclofenac), antidepressants, and opioids, although none of these medications is commonly used clinically.25

Only 2 medications are transdermally administered to manage pain. Fentanyl, a synthetic opioid agonist that interacts primarily with the μ-opioid receptor, has the appropriate properties for transdermal delivery including low molecular weight, high potency, and high lipid solubility. This agent is most commonly used in cancer pain. Most studies showed equal or improved pain relief compared with other long-acting opiates, with a tendency toward a reduction in side effects, most notably, constipation. If opiates are to be prescribed for a patient with CRPS, a trial of transdermal fentanyl is a reasonable option. In particular, one should consider whether the patient has intolerable side effects with other opiates. Clonidine, a centrally acting alpha-2 agonist, has a transdermal application for hypertension. It is useful in some pain conditions, including DPN, sympathetically maintained pain, and peripheral nerve injury. The mechanism of action for pain modulation by clonidine is not completely understood. Various investigations have supported peripheral, spinal, and supraspinal sites of activity. The relative contributions of systemic and localized effects are unclear. If a component of sympathetically maintained pain is present in the CRPS patient, then a trial of transdermal clonidine is reasonable.26, 27

The use of muscle relaxants in pain conditions is fraught with confusion. One class of medications, the so-called “skeletal muscle relaxants,” is approved for use in acute low back pain. This includes carisoprodol, metaxolone, methacarbamol, orphenadrine, and cyclobenzaprine. The exact mechanism of action for these heterogeneous drugs is not fully understood. Their therapeutic efficacy may be related to their sedative properties. In humans, skeletal muscles are not directly relaxed by these agents. Animal models have shown potential modulation of pain pathways that is independent of skeletal muscle relaxation. Of particular concern is carisoprodol. This agent has a metabolite meprobamate that because of its addictive properties has been classified as a controlled substance. Carisoprodol does not share this federal designation, but many states legislate its restrictive use. Cyclobenzaprine is chemically related to the tricyclic antidepressants and has a similar profile for overdose situations. Minimal evidence exists for the use of these medications in chronic neuropathic pain conditions.28, 29

A second class of medications is the antispasticity medications used to decrease muscle hypertonicity in the upper motoneuron condition. These medications include baclofen, tizanidine, and dantrium. Baclofen and tizanidine modulate hypertonicity through centrally mediated actions, whereas dantrium exerts its therapeutic effect directly at the level of the muscle. There is little evidence to support the use of dantrium for painful conditions. Anecdotal and animal model evidence exists for pain modulation with baclofen (both via oral and intrathecal delivery) and tizanidine. Baclofen, a γ-aminobutyric acid-B (GABA-B) agonist, is an inhibitory neurotransmitter at the level of both the brain and the spinal cord. Baclofen’s mechanism of action for pain reduction is not completely understood but may include sensory, motor, and autonomic interactions. Tizanidine, which is chemically similar to clonidine, probably exerts its antinociceptive effects at the spinal and supraspinal level. The use of this medication class to address neuropathic pain is reasonable, but these drugs should probably be considered as second-line agents.30

Anticonvulsants are perhaps the best-studied medication class for neuropathic pain. These agents exert their therapeutic effects through various mechanisms, including decreasing neuronal excitability by blocking sodium or calcium channels, by enhancing the inhibitory effects of GABA, or by inhibiting excitatory glutaminergic transmission. Although 3 older anticonvulsants (phenytoin, carbamazepine, valproic acid) have reported effectiveness in painful conditions, the use of newer anticonvulsants has expanded in the last 2 decades (appendix 1). Gabapentin has the largest clinical experience of the newer anticonvulsants. Its efficacy for both PHN and DPN is backed by large randomized controlled trials (RCTs). For CRPS, 1 such trial31 did not detect a significant effect with gabapentin, whereas a case series26 did suggest efficacy for that application. One RCT that supports the use of gabapentin in mixed neuropathic pain conditions likely includes patients with CRPS in the study population. Perhaps the largest therapeutic advantage of gabapentin is the lack of any specific, life-threatening organ toxicity associated with its use. One RCT supports the use of carbamazepine in patients with CRPS. Other anticonvulsants have lower levels of evidence to support their use both for neuropathic pain in general and CRPS specifically. Interestingly, there is a small case series that suggests that CRPS (then termed reflex sympathetic dystrophy) was caused by anticonvulsant use. The medications described in this series include phenytoin, carbamazepine, and phenobarbital.26, 32

No treatment for chronic neuropathic pain evokes more controversy than the use of opiates. Although their use in persons with acute pain is undeniable, their utility in the chronic phase is less clear. Opiates exert their therapeutic effects through modulation of both central and peripheral pain pathways. Several well-designed studies suggest efficacy of opioids in chronic neuropathic pain. However, 1 RCT failed to show benefit for patients with CRPS.26 Some of the medications studied in these trials are controlled-release morphine, controlled-release oxycodone, and transdermal fentanyl. There are minimal data comparing the utility of 1 opiate to another. Although all currently available opiates have activity at the μ-opiate receptor, methadone has activity both at this receptor and at the N-methyl-d-aspartate receptor. There is some suggestion that this modulation of the latter receptor can affect neuropathic pain, thus making methadone an attractive option. One randomized, placebo-controlled crossover study showed the synergetic effectiveness of controlled-release morphine with gabapentin for a mixed neuropathic pain population.33 Compared with nociceptive pain, it is generally thought that neuropathic pain requires higher doses of opiates for effective relief. Some data suggest that long-term opiate use can induce allodynia and hyperpathia. Opiate use is complicated by side effects (constipation, edema, altered cognition, hormonal suppression), abuse potential, and regulatory restrictions. Practitioners should be aware of these challenges if they intend to include chronic opiate use in their treatment algorithm.33, 34

Independent of their antidepressant effects, the tricyclic antidepressants (TCAs) have a long history of utility in chronic pain, with specific usefulness in neuropathic pain. Several well-designed controlled studies have shown their effectiveness.35 These agents inhibit neuronal reuptake of the neurotransmitters serotonin and noradrenalin; this inhibition in turn enhances the effect of the descending analgesic system. It appears that TCAs are better agents for pain modulation than are selective serotonin reuptake inhibitors (SSRIs) because they inhibit reuptake of both serotonin and norepinephrine, whereas SSRIs inhibit only serotonin reuptake. Side effects of the TCAs include sedation, confusion, constipation, urinary retention, weight gain, lowering of the seizure threshold, orthostatic hypotension, and serious cardiac arrhythmias. The elderly patient may be especially prone to these side effects. The drug concentration in the blood should be monitored to avoid toxicity in patients who are slow drug metabolizers. There are little data correlating the effectiveness of pain relief with plasma levels. Similar to the TCAs, serotonin-norepinephrine reuptake inhibitors appear to be more effective than SSRIs for treating neuropathic pain because they also inhibit reuptake of both norepinephrine and serotonin. The newest medication in this class is duloxetine, which has FDA approval both for depression and diabetic peripheral neuropathy. The pain-relieving effect for duloxetine also appears to be independent of its antidepressant activity. Side effects of duloxetine include sedation, confusion, hypertension (perhaps from increased synaptic norepinephrine), and a potentially challenging withdrawal syndrome. Because of the latter scenario, it is recommended that duloxetine be weaned over the course of no less than 2 weeks.19 Tramadol is a unique agent because it has dual activity: (1) as an agonist at opiate receptors and (2) as a modulator of the GABAergic, noradrenergic, and serotonergic systems.36 The use of antidepressants in neuropathic pain is certainly a reasonable therapeutic option. The newer agents appear to have a safer side-effect profile than the more traditional agents.35

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5.3 Clinical Activity: To manage painful trigeminal neuralgia in a 34-year-old patient with multiple sclerosis 

The presentation of pain in the patient with multiple sclerosis (MS) assumes many forms. As with all pain syndromes, an appropriate diagnostic assessment is warranted. Although the precise prevalence is unknown, individuals with MS can be afflicted with painful conditions that are unrelated to the MS (eg, lumbar radiculopathy, degenerative disk disease, osteoporosis). Treatment of these conditions is performed concurrently with the appropriate consideration of the neurologic impairment that is caused by multiple sclerosis.37 For example, the application of the heating modalities can be a reasonable treatment for musculoskeletal conditions. In the patient with MS, heat can cause increased weakness or fatigue (Uhthoff phenomenon). If the painful paresthesias are considered directly related to MS, they are probably associated with ectopic excitation at the site of demyelination. For example, lesions in the dorsal horn of the spinal cord can result in unpleasant tingling paresthesias and Lhermitte sign. Also, lesions in the trigeminal entry zone in the brainstem can lead to trigeminal neuralgia, a common pain syndrome in MS.

Perhaps the pain syndrome best studied in this population is trigeminal neuralgia. A number of reports have shown the effectiveness of anticonvulsants for this condition, with carbamazepine, gabapentin, and lamotrigine being discussed most commonly. Additionally, anticonvulsants are reported to have beneficial effects in other MS-neuropathic pain conditions such as glossopharyngeal neuralgia. The details of anticonvulsant use in neuropathic pain are reviewed elsewhere in this study guide. Other than for trigeminal neuralgia, the evidence-based support for the use of anticonvulsants in central MS-related neuropathic pain is low.38

Other treatments for MS-related pain similarly have a low level of evidence. A small case series supports the use of misoprostol. TCAs are mentioned in review articles but only have anecdotal evidence to support their use. The TCA’s side-effect profile may be especially problematic for the MS patient. The use of this medication class is reviewed in section 5.2 above.39

Thus, although descriptions of potential pharmacologic interventions for MS-related pain exist, RCTs that show the efficacy for most of these interventions are lacking.40 The lack of evidenced-based standards may suggest to the physiatrist to look at the broader pain treatment literature for suggestions pertinent to addressing pain in the patient with MS.

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Appendix 

Appendix 1. RECENTLY AVAILABLE ANTICONVULSANTS FOR NEUROPATHIC PAIN
Trade NameGeneric Name
ZonegranZonisamide
FelbatolFelbamate
TopamaxTopiramate
GabitrilTiagabine
LamictalLamotrigine
LyricaPregabalin
TrileptalOxcarbazepine
KeppraLevetiracetam
NeurontinGabapentin

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 No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated.

 Reprints are not available from the author.

PII: S0003-9993(07)01849-7

doi:10.1016/j.apmr.2007.12.002

Archives of Physical Medicine and Rehabilitation
Volume 89, Issue 3, Supplement 1 , Pages S56-S60, March 2008

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