The management of chronic pain can be divided into pharmacologic and nonpharmacologic therapeutic modalities.
Pharmacologic Treatment
Medications used for the treatment of pain are listed in Table 1.
Nonsterioidal anti-inflammatory drugs (NSAIDs). With increasing doses, all NSAIDs reach a limit to their maximum analgesic effect.[1] Although their effectiveness has been proved in acute pain syndromes that are inflammatory, their efficacy in controlling chronic pain is not well established.[2,3] Although some patients with chronic pain may respond better to one NSAID than to another, the value of these agents is related only to their adjunctive effects when combined with other treatments. A new class of NSAIDs has been introduced that selectively inhibits cyclooxygenase 2 (Cox 2) while sparing Cox 1.[9] Celecoxib is the first of the family of this new class of medication that selectively limits some of the side effects of the traditional NSAIDs.[10] Table 2 compares the incidence of side effects between the nonselective and Cox 2 selective NSAIDs.[11,12]
Aspirin and other salicylates. These drugs inhibit homeostasis and prolong bleeding time, and a single dose of aspirin can precipitate aspirin-sensitive asthma. Multiple doses can also lead to gastropathy and salicylism.[3] The adverse effects of aspirin are similar to those of all NSAIDs except for the risk of precipitating asthma and anaphylactoid reactions in aspirin-sensitive patients.
Acetaminophen. This drug is effective in most types of pain and can also exhibit its effect in single analgesic doses.[6] Although acetaminophen does not cause the characteristic side effects of NSAIDs, an overdosage can cause serious and fatal hepatic complications. Patients who do not have active liver disease and patients who do not abuse alcohol are also advised to lower acetaminophen exposure to minimize its potential hepatic toxicity.[3,13]
Combinations. Nonsterioidal anti-inflammatory drugs and acetaminophen can be given with opioids for an additive analgesic effect and to lower opioid doses. However, there is no evidence that NSAIDs have an additive effect when used with each other.[4,11]
Opioids. Up to about a decade ago, it was the understanding that opioids played no role in the management of chronic nonmalignant pain. It has now become more acceptable that opioids are one facet of well-integrated treatment of chronic pain. Table 3 summarizes the analgesic potency of some opioids in comparison with morphine.
Opioid agonists. These compounds include propoxyphene, codeine, oxycodone, hydrocodone, morphine, hydromorphine, meperidines, methadone, fentanyl, and levorphanol. Codeine, oxycodone, and hydrocodone are generally available in combinations with aspirin or acetaminophen.[3,13] Because of aspirin's effects on renal function and acetaminophen's hepatotoxicity, a limit on the analgesic effects of the accompanying opioid could occur, thus leading to the use of one opioid alone or to the use of another opioid.[13] Morphine, hydromorphine, and fentanyl have unique properties that can be tailored to benefit each individual pain sufferer.[16] Of particular value is fentanyl, which has been used in transdermal, sublingual, and intranasal forms. The transdermal form is absorbed slowly, requiring 12 to 24 hours to peak, and then gives persistent serum levels for as long as 17 hours after patch removal.[17]
Partial agonists and mixed agonist-antagonists. Buprenorphine is a partial agonist, pentazocine, nalbuphine, and butorphanol are mixed agonist-antagoinsts. These agents in general have limited use in the treatment of chronic pain because of their ceiling analegsic effect (ie, as their dose increases the analgesic effect remains the same).[15,16]
Tramadol. This analgesic opioid can be used in healthy adults at a dosage of up to 400 mg/day in divided doses every 4 to 6 hours, and dosage adjustment is necessary only in elderly patients more than 75 years of age for whom the maximum dose is 300 mg daily.[18] Tramadol has been reported to have a potential for drug abuse and may interact with the selective serotonin reuptake inhibitors (SSRIs). Seizures have been reported in patients using SSRIs and tramadol combinations.[18]
Opioid dose requirements vary widely among patients. When the optimal adequate analgesic dosage is reached through titration, it is usually effective for an average of 4 hours. It should be given on a regular schedule, with the provision that the patient can refuse a dose if not in pain.[13] "By-the-clock" administration of analgesics is much more effective than waiting for the next episode of pain to occur before administering the next dose, and an order for a supplementary dose between regular doses should be available for backup or breakthrough pain.[6,19]
The main adverse effects of opioids include sedation, dizziness, grogginess, nausea, vomiting, and constipation. Constipation needs to be addressed at the onset of treatment with the initiation of an appropriate bowel regimen. Insomnia, which is a frequent complaint of patients with chronic pain, may worsen with opioid treatment and needs to be addressed with early intervention.[15]
Tolerance is common with long-term use of opioids. Patients will first have shorter duration of analgesia and then an increase in pain levels.[14] Cross-tolerance exists among all of the opioid agonists, but it is not complete, and switching to another opioid starting with half the equianalgesic dose may be helpful.[13] Patients maintained on opioids for an extended period will have physical dependence and withdrawal phenomenon if the medication is abruptly discontinued or if an opioid antagonist is administered.
It is important to differentiate between opioid dependence and addiction. Addiction is a psychologic disorder and implies an overwhelming involvement with the use of the drug and extraordinary efforts to secure its supply (including robbery and other crimes). Increased risks of relapse into drug use after discontinuance and precipitation of opioids' withdrawal also occur in addicted patients. The majority of patients who are treated with opioids for acute pain or cancer pain rarely become addicted to the mood-altering or euphoric effects of the opioids. The only absolute contraindication for opioid use is allergy. Opioids can be lethal in cases of drug overdosage because of their respiratory depressant effects. Patients without pulmonary disease who are maintained on opioids for a long time become tolerant to their respiratory depressant effect, but the addition of general anesthetics, neuroleptics, sedative-hypnotics, tricyclic antidepressants, or other central nervous system (CNS) depressants would increase the risk of respiratory depression.[13,15]
When making the decision to treat chronic pain with opioids, primary care physicians need to comply with the Drug Enforcement Administration regulations, as well as individual state guidelines. It is also important to know that most of the state medical boards have now accepted the use of opioids in chronic nonmalignant pain as described in the guidelines issued by the American Pain Society.[20]
Antidepressant mdications. Most patients with chronic pain could benefit from antidepressants, especially if they have comorbid psychiatric conditions such as depression, sleep disorders, psychologic factors affecting physical conditions, anxiety, somatization disorder, or somatoform pain disorder.[7,8] Antidepressants have also proved to be effective in treating a variety of painful conditions such as cancer, arthritis, headache, diabetic neuropathy, postherpetic neuralgia, phantom limb pain syndrome, postoperative pain, peripheral neuralgia, chest wall pain, fibromyalgia, vasculitic neuropathy, and low back pain.[7,8] In addition, antidepressants have been effective and widely used for the treatment of atypical facial pain and have some usefulness in treating trigeminal and glossopharyngeal neuralgia.[8,21] Although the antidepressant effect takes several weeks, pain relief may occur within a week.[22,23] Side effects of tricyclic antidepressants (TCAs)[7] include anticholinergic effects of dry mouth, blurred vision, urinary retention, constipation, orthostatic hypotension, sexual dysfunction, tremors, disturbed sleep, and rarely nocturnal myoclonus.[23] The anticholinergic and quinidine-like effects of TCAs make them relatively contraindicated in patients with cardiac conditions.[22,23] The sedative properties of TCAs may also require dosage scheduling to be tailored to each individual patient. Tricyclic antidepressants have a relatively narrow therapeutic/toxic dose ratio and can be lethal in case of overdosage.[8,23] Trazodone, with its main side effect of orthostasis and a low incidence of priapism, is an alternative antidepressant for treatment of chronic pain.[24] The SSRIs have a milder side effect profile, which may include headache, somnolence, nervousness, nausea, fatigue, tremor, and sexual side effects.[25]
Anticonvulsants and benzodiazepines. The value of anticonvulsants such as phenytoin, carbamazepine, valproate, and gabapentin in decreasing neuropathic pain have been well established.[26] Several clinical studies have documented the effectiveness of these medications in treating chronic pain associated with diabetic neuropathy and postherpetic neuralgia, as well as sharp and lancinating pain.[7,26] Gabapentin, which has minimal side effects, is considered a breakthrough primary adjunct agent for chronic pain management and can offer the best advantage in most clinical settings.[27] The CNS effects of anticonvulsants, especially ataxia and drowsiness, tend to be dose related and occur early in treatment. Sedation can be usually managed by giving most of daily dose at bedtime. Careful monitoring of side effects is indicated if the anticonvulsants are administered with other CNS depressants, especially in the elderly. When anticonvulsants are used for the treatment of chronic pain, the dose is titrated and increased as tolerated, depending on the emergence of side effects rather than on the anticonvulsant blood levels.[7] Another anticonvulsant, clonazepam, is a benzodiazepine that can be administered in small divided doses of up to 4 mg daily. Clonazepan has shown effectiveness in the treatment of chronic lancinating pain, with the advantage of having fewer side effects.[28]
Antihistaminics. Hydroxyzine and other antihistaminics in injectable doses of 50 to 100 mg have potentiated the analgesic effect of opioids during acute exacerbation of chronic pain.[3,6] Although antihistaminics are rarely used, they are considered a rescue in drug-seeking patients only.[8]
Corticosteroids. These agents rarely have a use in chronic pain, but their anti-inflammatory effects can achieve analgesia in some patients with chronic pain and inflammatory diseases (eg, rheumatoid arthritis) or in patients who have tumor infiltration of nerves.[8,11]
Membrane-stabilizing agents. Tocainide and mexiletine are oral agents that can at times be used to treat chronic neuropathic pain. Mexiletine is usually preferred over tocainide, which has been associated with the development of anemia. Some patients with chronic pain may respond to the analgesic effects of intravenous lidocaine. Lidocaine-sensitive pain is diagnosed by administering a 100 mg bolus dose intravenously or 4 mg/kg over 30 minutes. The analgesic effect is then monitored with the use of a visual analogue scale.[29]
Topical agents.[30] Capsaicin is a commonly used topical medication that can reduce pain sensations in some patients. It is available as a nonprescription medication in 0.025% and 0.075% concentrations. This medication acts on the depletion of an endognous peptide through the release of substance P, which is involved in the transmission of pain messages from the peripheral organs to the CNS. It takes several weeks for capsaicin to achieve a result. It can cause some irritations with burning, and patients need to wash their hands thoroughly after touching the cream or lotion. It must also be kept away from eyes and mucous membranes. Capsaicin is usually most effective when used as an adjunct to systemic medications.
Among the volatile solvents such as chloroform or ether, paste of aspirin has been also used as an adjunctive agent for topical management of postherpetic pain. The NSAIDs indomethacin and diclofenac may be also used topically, and they presumably decrease the elevated postaglandin tissue levels that occur with cutaneous pain.
Clonidine.[30,31] This a2-adrenergic agonist produces analgesia when administered intrathecally, epidurally, or systemically. It is useful in patients who have tolerance to opiates. It is available in both the oral form and a transdermal patch.
Muscle relaxants. Agents that lead to muscle relaxation, such as methocarbamol, baclofen, and cyclobenzapine, have been used to decrease generalized muscle pain in patients who have fibromyalgia as well as chronic pain due to increased muscle spasm.
Pain Clinics
The role of pain clinics in managing chronic pain as a disease with its own incidence, epidemiology, assessment, and treatment is becoming an important facet of the heritage and practice of medicine.[1] The interdisciplinary pain clinics use multiple modalities such as physical therapy, exercise, vocation evaluation, and individually designed rehabilitation programs.[27] Pain clinics function as an interface between primary care, psychiatry, neurology, psychology, behavioral medicine, and occupational and physical therapy.[3,4] In addition to their cost effectiveness, pain clinics play a role in reducing unreasonable expectations by taking patients off the multiple and sometimes conflicting pain medications and promoting the resumption of tolerable physical activities.[8]
Surgical Treatment of Chronic Pain
Before the use of invasive surgical procedures for the treatment of chronic pain, local anesthetic nerve blocking can be done to aid in localizing the source of pain and can also achieve therapeutic benefits.[32] Several surgical procedures, including sympathetic blockade can be done at the stellate, lumbar, or celiac ganglia.[32] Procedures such as injecting absolute alcohol or phenol and the neruosurgical cordotomy or rhizotomy, which permanently destroys neural structures, can also predict the prognostic effect of local anesthetic. These procedures allow the patient to temporarily experience the sensation that will follow the permanent procedure.[32] If local anesthetics and sympathetic blockade fail to provide long-term pain relief, then electrical stimualtion of the spinal cord or "dorsal column stimulation" can be introduced as another option for relief of intractable pain.[32,33] Radiofrequency ablation and newer minimally invasive surgical procedures can also substantially reduce chronic pain.[33] Narcotics delivered neuroaxially either into the epidural space or distally (intrathecally) into the spinal fluid can also offer pain relief when other forms of treatment have failed.[3,33] The key for a good prognostic outcome in surgical intervention is the proper selection of patients. A frank discussion of each procedure should be conducted with both patient and family, with special emphasis on side effects and the realistic expectations of benefits of the procedure.[30] It is important to understand that surgical procedures and ensuing pain control will not necessarily treat the underlying medical conditions.[30,32]
Nonpharmacologic Treatment of Chronic Pain
Transcutaneous electrical nerve stimulation (TENS). In selected patients the appropriate use of TENS can achieve some reduction of pain.[2] Although TENS units allow patients to restore their sense of self-control and reduce the risks associated with systemic medications, in long-term studies their use has not been shown to enhance functioning.[6,13]
Psychotherapy
Individual and group psychotherapy engages patients with chronic pain in developing cognitive and behavioral coping skills and can be effective in limiting the psychologic disability that is induced by pain.[1] Efforts to improve a patient's ability to cope are usually more effective when they include family members and significant others.[4,6] Education, counseling, relaxation training, biofeedback, and conflict resolution over autonomy and care are necessary components in addition to the technical aspects of any psychotherapeutic interventions.[3,8] Hypnosis can also be used in some selected cases of chronic pain.[8,27]
Spiritual Intervention
Spiritual support for the patient with chronic pain is another facet of the multimodal treatment approach. The spiritual dimension of treatment incorporates the patient's religious beliefs and spiritual orientation into regaining hope and developing a sense of control over pain through prayer, meditation, church or synagogue attendance, and other devotional practices.[34]
Rehabilitation
Rehabilitation efforts should aim at allowing patients to perform their normal activities within a year of pain onset.[7] Delays resulting from the performance of diagnostic evaluations, and pursuing workers' compensation may adversely affect the enhancement of functioning. In workers' compensation cases, the patient especially needs to obtain impairment evaluation and functional capacity examination to initiate immediate interventions that could achieve maximal medical improvement.[13,27] The interdisciplinary team approach to rehabilitation combines palliative care and physical rehabilitation and explores multiple treatment methods tailored to each individual patient's particular circumstances.[3,13]
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