Abstract
Complex regional pain syndrome (CRPS), previously known as reflex sympathetic dystrophy and causalgia, poses a challenge to treating clinicians. Multiple pain pathways are thought to be involved in driving the condition. Medication management should focus on targeting these various pathways to improve efficacy. Unfortunately, strong evidence is lacking for the majority of medication treatment options. Corticosteroids are supported early in the acute phase of the disease. Although gabapentin and pregabalin lack strong evidence, they are commonly prescribed because of their tolerability and safety profile. Chronic opioid therapy should be used cautiously secondary to addiction risk and long-term tolerance.
This chapter focuses on the available oral and topical pharmacotherapy options in the treatment of CRPS. The mechanism of action, available evidence, dosages, and side effects/complications are discussed for each class of medication.
Keywords
Causalgia, Complex regional pain syndrome, Management, Medication, Medicine, Pharmacotherapy, Reflex sympathetic dystrophy
Introduction
Complex regional pain syndrome (CRPS) poses a significant challenge to the treating clinician. Not only is CRPS difficult to recognize and diagnose, but there is also paucity of effective, evidence-based treatments for the condition. CRPS typically presents with pain out of proportion to the mechanism of injury, with varying degrees of motor and sensory changes, sudomotor activity, vasomotor activity, autonomic dysfunction, and atrophy of the affected region. Because of the various pain pathways hypothesized in driving the syndrome, multiple medications in different classes are usually necessary for effective control. Not only does this help to minimize medication side effects by enabling lesser doses of medication, but also multiple pain pathways are blocked, which improves efficacy of treatment. This chapter focuses on oral and topical pharmacotherapy prescribed for the treatment of CRPS.
Antiinflammatories
Injury to an extremity, such as fracture or sprain, or injury to a nerve commonly precedes the development of CRPS. Exaggerated local inflammation of the injured tissue is postulated to play a role in the development of CRPS. Cytokines, including interleukin (IL)-1, tumor necrosis factor-α, and nerve growth factor, are elevated and sensitize the local tissue, whereas calcitonin gene-related peptide and substance P mediate the pain response. This theory has popularized the utilization of antiinflammatory medications in the treatment of CRPS.
Corticosteroids reduce inflammation by inhibiting cytokines and pain mediators. Their utility in the treatment of CRPS has been questioned. Often they are not offered when a fracture is involved, as there is fear of delayed bone healing with the initiation of glucocorticoids; however, one small case report showed efficacy in the setting of a fracture without adverse events. There is evidence supporting the utilization of corticosteroids in the treatment of CRPS. Most studies suggest that the steroid be started in the first 3 months of appearance of symptoms, with a high dose tapered to a lower dose over 2 weeks and then a slow taper off of the steroid for a total treatment length of 4–12 weeks. The use of steroids for the treatment of chronic CRPS (>3 months) has less support. Steroid treatment in CRPS following stroke is supported by multiple studies that led to improvement in pain and function. Complications are listed in Table 8.1 . Caution is advised in the treatment of patients with diabetes, hypertension, glaucoma, or a history of gastrointestinal (GI) bleed/ulceration. Long-term exposure to corticosteroids carries a risk of osteoporosis and cataract formation.
| Medication | Dosage | Complications |
|---|---|---|
| Corticosteroids | ||
| Prednisone | 5–60 mg/day po | Facial flushing, hot flashes, GI upset, swelling, insomnia, weight gain, hyperglycemia, HTN, nausea/vomiting, dizziness, and emotional lability GI bleed, GI perforation/ulceration, adrenal insufficiency, Cushing syndrome, diabetes mellitus, pseudotumor cerebri, psychosis, avascular necrosis, and myopathy Osteoporosis, cataracts, immunosuppression (long-term use) |
| Prednisolone | 5–60 mg/day po divided qd-qid | |
| Methylprednisolone | 4–48 mg/day po divided qd-qid | |
| Dexamethasone | 0.75–9 mg/day po divided q6-12h | |
| Nonselective NSAIDs | ||
| Ibuprofen | 200–800 mg po tid-qid | GI upset, constipation, fluid retention, headache, diarrhea, nausea/vomiting, rash, dizziness, ALT/AST elevation, BUN elevation, photosensitivity GI bleeding, GI perforation/ulcer, MI, stroke, thromboembolism, HTN, CHF, nephrotoxicity, hepatotoxicity, bronchospasm, Stevens-Johnson syndrome |
| Diclofenac | 50 mg po tid | |
| Etodolac | 200–400 mg po q6-8h | |
| Fenoprofen | 300–600 mg po tid-qid | |
| Indomethacin | 25–50 mg po bid-tid | |
| Ketoprofen | 50 mg po q6-8h | |
| Ketorolac | 10 mg po q4-6h | |
| Meloxicam | 7.5–15 mg po qd | |
| Nabumetone | 1000-2000 mg/day po divided qd-bid | |
| Naproxen | 250–500 mg po q12 h | |
| Oxaprozin | 1200 mg po qd | |
| Piroxicam | 20 mg po qd | |
| Sulindac | 150–200 mg po bid | |
| Tolmetin | 200–600 mg po tid | |
| Celecoxib (COX-2 inhibitor) | 200 mg po divided qd-bid | |
| Free Radical Scavengers | ||
| Dimethylsulfoxide | 50% cream to affected extremity 5×/day | Skin reaction, rash, headache, dizziness, drowsiness, strong odor |
| N -acetylcysteine | 600 mg effervescent tablets po tid | Nausea/vomiting, diarrhea or constipation, potential bronchospasm in asthmatics |
| Vitamin C | 500 mg po daily for 50 days after wrist fracture | Nausea/vomiting, dyspepsia, diarrhea, headache |
Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in the treatment of pain. They work by blocking the cyclooxygenase (COX) pathway and the formation of prostaglandins that mediate the inflammatory response. NSAIDs may block prostaglandins at the spinal level, suppressing the nociceptive pathway. Nonselective NSAIDs block both COX-1 and COX-2. Diclofenac 50 mg twice a day for 1 month showed improvement in pain and hand function in one study. Selective NSAIDs block only COX-2 and gained popularity because of a better GI safety profile. However, there is lack of evidence for their use in CRPS. Complications are listed in Table 8.1 . NSAIDs are associated with an increased risk of cardiovascular events. It is recommended that kidney function, liver function, and blood pressure be monitored with the continued use of NSAIDs.
Free radical scavengers are utilized to reduce the inflammatory response by eliminating free radicals released during the inflammatory response. Dimethylsulfoxide 50% in a fatty cream and N -acetylcysteine tablets lead to improvement in pain and function in patients with CRPS. A study performed by Zyluk et al. revealed a positive outcome with the use of mannitol in patients with CRPS, but their study had no placebo group and patients were coadministered dexamethasone. Prevention of CRPS with daily vitamin C has been studied in patients with wrist fractures, and a lower incidence of CRPS was found in the treatment group. The above-mentioned treatments were well tolerated and did not result in significant side effects.
Antiepileptics
Gabapentin is widely used for the treatment of neuropathic pain. It also has an indication for controlling partial seizures. It is hypothesized to work by binding to the α2δ subunit of the voltage-gated calcium channel, thus decreasing the release of excitatory neurotransmitters. Treatment of painful diabetic neuropathy and postherpetic neuralgia are two proven uses for gabapentin. Two randomized controlled trials of gabapentin have been performed in the population with CRPS. The larger study included 307 patients, of which 85 had the diagnosis of CRPS, and the smaller study included 58 patients with CRPS. The first study revealed a small but statistically significant reduction in pain in the gabapentin-treated group. The second study led to early but only short-term reduction in pain in the treatment group. However, gabapentin did provide long-term improvement of sensory deficits in the affected limb.
Gabapentin is commonly prescribed three times a day with a maximum dose of 3600 mg/day. The initial dose is low and is titrated upward until there is a positive therapeutic effect. Complications are listed in Table 8.2 .
| Medication | Dosage | Complications |
|---|---|---|
| Gabapentin | 300–1200 mg po tid | Somnolence, dizziness, fatigue, dry mouth, peripheral edema, weight gain, gastrointestinal upset, tremor Depression, suicidal ideation, and withdrawal seizure (abrupt discontinuation) |
| Pregabalin | 150–600 mg po divided bid-tid | Dizziness, somnolence, dry mouth, peripheral edema, blurred vision, weight gain, constipation Suicidality, depression, withdrawal seizure (abrupt discontinuation) |
| Carbamazepine | 200–400 mg po bid | Dizziness, drowsiness, urticaria, nausea/vomiting, constipation, ataxia, rash, blurred vision, tremor, speech difficulty Aplastic anemia, fatal dermatologic reaction, hepatotoxicity, thrombocytopenia, leukopenia, hyponatremia, Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
| Oxcarbazepine | 300–1200 mg po bid | Fatigue, dizziness, ataxia, and nausea/vomiting, tremor, diplopia, balance difficulty Hyponatremia, SIADH, toxic epidermal necrolysis, thrombocytopenia, leukopenia, pancreatitis |
| Topiramate | 50–400 mg po divided bid | Weight loss, somnolence, nausea, diarrhea, paresthesias, tremor Metabolic acidosis, osteoporosis, hypokalemia, suicidality, hyperthermia |
Pregabalin is a newer antiepileptic medication with a similar mechanism of action as gabapentin. It has gained popularity because of its twice daily dosing and linear pharmacokinetics that allows faster titration. Pregabalin has supporting evidence for its use in painful diabetic neuropathy and postherpetic neuralgia. Research on this agent is lacking in the population with CRPS. One case report revealed resolution of pain within 2 days of initiating pregabalin in a patient who failed to improve after treatment with physical therapy, gabapentin, and multiple stellate ganglion blocks. The side-effect profile of pregabalin (see Table 8.2 ) is similar to that of gabapentin and tolerated well.
Sodium channel antagonists are another treatment consideration. Carbamazepine is approved by the US Food and Drug Administration (FDA) for the treatment of trigeminal neuralgia. A small study showed support in treating the population with painful diabetic neuropathy. Carbamazepine was compared with morphine in treating CRPS after the spinal cord stimulator of a patient with CRPS was turned off. Carbamazepine given 600 mg/day led to a delayed and reduced level of pain after 8 days, and there was no effect in the morphine group. Larger studies need to be performed before conclusions can be drawn. Complications are listed in Table 8.2 .
Oxcarbazepine has a similar mechanism of action as carbamazepine but has not been studied in the population with CRPS. There is one placebo-controlled trial that led to a reduction of pain in 146 patients with painful diabetic neuropathy treated with a maximum daily dose of 1800 mg. Side effects and adverse events are listed in Table 8.2 . Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia may develop in patients treated with both carbamazepine and oxcarbazepine.
Topiramate is employed as an anticonvulsant as well as for migraine prophylaxis. Its exact mechanism of action is unknown, but it is thought to block sodium channels, antagonize γ-aminobutyric acid activity, block glutamate receptors, and inhibit carbonic anhydrase. One study revealed efficacy in treatment of painful diabetic neuropathy. When treatment is initiated, the dosage should be started at a low level and titrated slowly to a maximum dose of 400 mg/day. Complications are listed in Table 8.2 .
Antidepressants ( Table 8.3 )
Tricyclic antidepressants (TCAs), such as nortriptyline, amitriptyline, and desipramine, have been used extensively in the treatment of neuropathic pain. Elevated levels of norepinephrine and serotonin inhibiting the dorsal horn and partial sodium channel blockade are the proposed analgesic mechanisms of action. Their use in the treatment of CRPS is by convention and based on expert opinion. A low starting dosage is recommended with a slow titration. An adequate trial can take up to 2 months before considering treatment failure. Common side effects are listed in Table 8.3 .
| Medication | Dosage | Complications |
|---|---|---|
| Tricyclic Antidepressants | ||
| Nortriptyline | 25–150 mg po qhs | Drowsiness, dry mouth, dizziness, constipation, blurred vision, nausea/vomiting, confusion, urinary retention, weight gain, libido changes, tremor Hypotension, cardiac arrhythmia, suicidality, extrapyramidal symptoms |
| Amitriptyline | 25–100 mg po qhs | |
| Desipramine | 25–200 mg po qd | |
| Doxepin | 25–300 mg po qhs | |
| Serotonin-Norepinephrine Reuptake Inhibitors | ||
| Duloxetine | 30–60 mg po qd | Nausea, headache, dry mouth, fatigue, constipation, dizziness, decreased libido, tremor Suicidality, depression exacerbation, withdrawal symptoms if abruptly discontinued |
| Venlafaxine | 75–225 mg po div bid-tid 75–225 mg ER po qd | |
The serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine and duloxetine, have been shown to benefit patients with neuropathic pain with the added potential of treating concomitant depression. Venlafaxine was shown to be equally effective to imipramine (TCA) in the treatment of painful polyneuropathy. Patients with painful diabetic neuropathy benefited from treatment with duloxetine in a multicenter trial. SNRIs have not been studied in the population with CRPS but have been used anecdotally. Side effects and complications are listed in Table 8.3 .
Selective serotonin reuptake inhibitors (SSRIs) are not beneficial in the treatment of neuropathic pain. They can be considered in treating underlying depression in the population with chronic pain.
Bisphosphonates
Bisphosphonates are potent osteoclast inhibitors that block bone resorption and are used in the management of osteoporosis, Paget disease, and cancer-related bone pain. Patients with CRPS commonly present with osteopenia in the affected limb and increased uptake of radiotracer on three-phase bone scan. Originally, interest in using bisphosphonates in the treatment of patients with CRPS was based on slowing bone resorption. However, newer theories suggest that high levels of bisphosphonates in local tissue prevent the production of hydroxyapatite crystals, reducing lactic acid production and modulating the local inflammatory response.
Five randomized controlled trials ( Table 8.4 ) in the population with CRPS have been performed to date. Four of these studies investigated intravenous bisphosphonates, and one investigated an oral bisphosphonate. The doses administered in each study were close to the recommended doses for bone metabolism disorders such as Paget disease or cancer-related bone pain, which is significantly higher than the dose used in treating osteoporosis. Dosing regimens were varied and follow-up was up to 3 months. All studies showed a positive outcome, with the treatment groups reporting less pain than the control group. Limitations of the studies include a small, heterogeneous patient population, various CRPS diagnostic criteria, and different outcome measures. The disease was chronic in all but one study.
| Investigator | Treatment Regimen | Number of Subjects | Follow-Up Length | Additional Treatments |
|---|---|---|---|---|
| Adami et al. | Alendronate 7.5 mg IV daily × 3 days versus IV placebo | 20 | 4 weeks | Physical therapy, calcitonin nasal spray, analgesics (unspecified) |
| Manicourt et al. | Alendronate 40 mg po daily × 8 weeks versus oral placebo | 40 | 24 weeks | Physical therapy |
| Robinson et al. | Pamidronate 60 mg IV × 1 dose versus IV placebo | 27 | 3 months | Paracetamol, codeine, paracetamol/dextropropoxyphene |
| Varenna et al. | Neridronate 100 mg IV q3 days × 4 doses versus IV placebo | 82 | 40 days | NSAIDs, paracetamol |
| Varenna et al. | Clodronate 300 mg IV daily × 10 days versus IV placebo | 32 | 180 days | None |
Common side effects of bisphosphonates include musculoskeletal pain, abdominal pain, and acid reflux. Serious adverse events include osteonecrosis of the jaw, atypical femur fracture, and gastric/duodenal ulcer. It is recommended that patients take a drug holiday after 5 years of treatment. Although the available data are weak, the use of bisphosphonates in treating CRPS is supported particularly in those patients with osteopenia. Because of the higher cost associated with intravenous administration, efficacy has to be supported with future studies.
Calcitonin
Calcitonin inhibits osteoclastic activity and has analgesic properties leading to its use in the population with CRPS. Unfortunately, there is no data to support its use in CRPS. Multiple studies investigated intranasal and intramuscular injections of calcitonin in the treatment of CRPS and found no benefit. A recent editorial by Benzon calls for the calcitonin studies to be repeated with validated diagnostic criteria and larger sample sizes. Intranasal administration is cost-effective and well tolerated, with the most common side effects being epistaxis and nasal irritation. Salmon allergy precludes the use of calcitonin.
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