ABSTRACT: The results of diagnostic tests do not correlate well with the presence and severity of pain. To avoid missing a serious underlying condition, look for "red flags," such as unexplained weight loss or acute bladder or bowel function changes in a patient with low back pain. Nonopioid medications can be more effective than opioids for certain types of pain (for example, antidepressants or anticonvulsants for neuropathic pain). When NSAIDs are indicated, cyclooxygenase-2 inhibitors are better choices for patients who are at risk for GI problems or who are receiving anticoagulants. However, if nonspecific NSAIDs are not contraindicated, consider using these far less expensive agents. The tricyclic antidepressants are more effective as analgesics than selective serotonin reuptake inhibitors. When opioids are indicated, start with less potent agents (tramadol, codeine, oxycodone, hydrocodone) and then progress to stronger ones (hydromorphone, fentanyl, methadone, morphine) if needed.
Pain is the complaint for which patients most often seek medical attention.1The Joint Commission on Accreditation of Health Care Organizations has officially recognized pain as a major health problem and has issued guidelines for its appropriate assessment and management.1 The guidelines were drawn up because multiple studies have shown that pain is often poorly managed.
Chronic pain can be especially difficult to treat. Unlike acute pain, for which there is usually a clearly identifiable cause, the causes of chronic pain are often complex.
Here I answer some of the most common questions clinicians have about the evaluation and pharmacologic management of chronic pain.
What is the best way to assess the severity of pain?
Although pain is a subjective complaint, there are a number of different instruments for assessing its intensity.2 Among the most commonly used are:
These scales have been shown to be equally accurate. Select the one that you find easiest to use.
All 3 scales can be used for both acute and chronic pain; however, certain instruments have been designed specifically to evaluate chronic pain. These instruments-which include the McGill Pain Questionnaire and the West Haven-Yale Multidimensional Pain Inventory-allow for a more in-depth analysis of a patient's pain. However, they are used more often in research than in clinical settings.
Clinicians sometimes worry that a patient may be exaggerating or even faking pain for financial gain. However, unless there is evidence that the patient is lying (as in malingering or factitious disorder), it is best to accept his or her pain complaint as real. Keep in mind that complaints of pain are common in many psychiatric disorders-most notably depressive and anxiety disorders-and that the pain associated with these disorders is as real as that secondary to physical pathology.
If I do not order diagnostic tests, how can I be sure that I will not miss a potentially serious condition?
2Patients with chronic pain often undergo a variety of diagnostic tests in an attempt to identify the cause of their pain and to quantify their suffering. However, multiple studies have shown that there is often little correlation between the results of diagnostic tests and the presence and severity of pain. One study, for example, demonstrated that if MRI scans of the lumbar spine are performed in a randomly selected group of persons who do not have low back pain, at least 1 abnormal disk will be identified in about 66% of the participants, and problems in 2 or more disks will be evident in almost 40% of them.3
The possibility of missing a serious underlying illness is a valid concern. However, studies have shown that for the 2 most common types of pain-low back pain and headache-there are a number of "red flags" that suggest the presence of organic pathology and signal the need for diagnostic testing.
The only condition associated with low back pain that must be treated as an emergency is cauda equina syndrome. Fortunately, this condition is relatively rare and the symptoms are usually easy to detect. These include:
Red flags for potentially serious conditions associated with headache include:
Although CT and MRI scans are often included in the evaluation of patients with migraine and tension-type headaches, such studies are usually not indicated for these conditions and provide no useful information about treatment.
Are opioids usually the best option for patients with chronic pain?
3Although the opioid analgesics are often thought of as "the best" pain medications, drugs from the other classes can provide equal or, at times, greater analgesia, depending on the cause of the pain. For example, pain that stems from bone pathology often responds better to NSAIDs than to opioids. Neuropathic pain that results from lesions in the peripheral or central nervous system is often better managed with antidepressants and anticonvulsants than with opioids. The triptans and ergots are used to treat migraine headaches. Finally, bear in mind that long-term opioid use can actually lower pain thresholds and exacerbate pain.4
Table 1 lists dosages and other prescribing information for the nonopioid agents most commonly used to treat chronic pain; these include NSAIDs, acetaminophen, antidepressants, and anticonvulsants. Table 2 lists prescribing information for the opioids.5
What is the optimal strategy for prescribing opioid analgesics?
4 A good approach is to start with less potent opioids and then progress to the stronger ones as-and if-needed.
Less potent opioids. These include:
Tramadol is a combination drug that contains a serotonin-norepinephrine reuptake inhibitor and a mild analgesic (1/5000 the strength of morphine). Codeine, oxycodone, and hydrocodone have comparable analgesic effects. Why certain patients respond to one better than another is not always clear.
Codeine, oxycodone, and hydrocodone are metabolized to their analgesic forms by the P-450 2D6 hepatic isoenzyme system. Codeine is metabolized to morphine, oxycodone to oxymorphone, and hydrocodone to hydromorphone. Thus, drugs that inhibit this isoenzyme system can markedly diminish the analgesic effects of these medications. The selective serotonin reuptake inhibitors (SSRIs), especially fluoxetine and paroxetine, are among the more widely used agents that inhibit P-450 enzymes.
Codeine, oxycodone, and hydrocodone are most commonly available in preparations that contain acetaminophen. Although patients can become tolerant of the analgesic effects of opioids and may in time require higher doses to manage their chronic pain, they do not become tolerant of the hepatic toxicity associated with acetaminophen. You can avoid problems with acetaminophen toxicity by giving the opioid alone, with separate dosing of acetaminophen. Both codeine and oxycodone are available in preparations that do not include any additional medications (hydrocodone is only available in combination with other medications, such as acetaminophen or ibuprofen).
Oxycodone is available in a sustained-release preparation that can be useful for patients who require opioids for an extended period. Although there has been much publicity about the abuse of this drug, it does not appear to be associated with more problems than the other opioids, if it is used correctly.
More potent opioids. These include:
Meperidine is generally contraindicated in all forms of chronic pain. Its metabolite, normeperidine, has a longer half-life than meperidine and therefore can accumulate with repeated dosing. Normeperidine is a cerebral irritant that can cause seizures and death. Meperidine also has the disadvantage of poor oral bioavailability.
Hydromorphone, fentanyl, methadone, and morphine can all be beneficial. Fentanyl is available in preparations that are absorbed transdermally or transmucosally. These can be especially useful for patients who have difficulty in tolerating oral medications, such as cancer patients with nausea and vomiting. The transdermal preparation of fentanyl is usually applied for 72 hours; the transmucosal form is used to manage breakthrough pain and not as the primary opioid analgesic.
Although methadone is usually regarded as an agent used to treat opioid addiction, it is an important analgesic. In addition to acting on the opioid receptors in the CNS, it also appears to provide analgesia by blocking the N-methyl-D-aspartate (NMDA) receptors. Although methadone has a long half-life (which is why it can be given once a day for the treatment of opioid addiction), its analgesic effect is more short-lived. Thus, for optimal analgesia, methadone must be given every 6 to 8 hours. When such a dosing schedule is used, methadone provides a stable level of analgesia comparable to that of the other longer- acting opioids-including controlled- release morphine.
There is no ceiling dosage for the µ-opioid receptor agonists (which include morphine, methadone, fentanyl, hydromorphone, codeine, oxycodone, and hydrocodone). Because patients may develop tolerance to the analgesic effects of these medications, increasingly higher doses may be needed over time to achieve the same level of pain relief.
If a patient requires more than 2 doses per day of an immediate-release opioid for an extended period, consider prescribing a long-acting opioid. These medications provide more stable analgesia over the course of a day than short-acting opioids. However, long-acting opioids must be taken on a fixed schedule to be effective. Long-acting opioids are not useful for acute pain because there can be a delay of several days before their maximum analgesia is achieved.
When you switch from a short-acting to a long-acting opioid, dose the long-acting medication conservatively at the beginning. This is especially important when a long-acting formulation of a different opioid is used.
In addition to the long-acting opioid, prescribe a short-acting one initially on an "as-needed" basis for breakthrough pain. Select the short-acting opioid based on the potency of the long-acting opioid. For example, hydromorphone can be useful for breakthrough pain in patients who take long-acting methadone, morphine, or fentanyl. Short-acting oxycodone is usually prescribed for breakthrough pain in patients who take the long-acting form of the same drug. Knowing the amount and frequency of breakthrough medication a patient uses can help you adjust the dosage of the long-acting opioid. After the first 1 to 2 weeks of use of a long-acting opioid, this drug should provide most of the analgesia the patient needs, with breakthrough medication required relatively infrequently and usually only during activities that acutely exacerbate the pain.
Is it legally safe to prescribe opioids for chronic pain?
5The use of opioids for chronic pain is legally safe as long as the medications are prescribed in accordance with the law and with accepted medical practice. Many states have adopted all or part of the model guidelines on the use of controlled substances for pain issued by the Federation of State Medical Boards of the United States.6 These guidelines clearly note that opioid analgesics have a legitimate place in the management of pain and that extended use may be required.
A hotly debated questionis whether patients with chronic pain who take opioid analgesics on a long-term basis become addicted to these medications. Unfortunately, there are relatively few studies on the subject. The study most often cited to indicate that abuse and addiction are infrequently encountered among patients treated with opioids was published by Porter and Jick7 as a letter to the editor in 1980. These researchers reported that opioid addiction developed in only 4 of about 12,000 patients who had received 1 or more doses of an opioid during hospitalization and who had no history of substance abuse. However, the authors did not try to differentiate between patients with chronic pain, those with acute pain, and those with a terminal illness.
In contrast, Bouckoms and colleagues8 studied 59 patients with chronic noncancer pain treated with opioid analgesics for an average of 36 months. They found that 24% of the participants became addicted to these medications. However, the authors were unable to discern any factors that could help predict which patients were more likely to have problems with opioids.
In my practice, it is not uncommon to see patients with chronic pain who either abuse or become addicted to opioid analgesics. This is not a reason to avoid prescribing opioids for pain. However, it does indicate that addiction is a potential problem. Monitor all patients who are being treated with opioids for signs of abuse or addiction. Such signs include:
Which antidepressants have the greatest analgesic effect?
6Antidepressants have been shown to provide analgesia for a wide range of chronically painful conditions, including neuropathic pain (such as that associated with diabetic neuropathy), osteoarthritis, rheumatoid arthritis, and irritable bowel syndrome. Antidepressants are particularly efficacious in the management of fibromyalgia9 and can provide prophylaxis for migraine and tension-type headaches as well.
Antidepressants that affect both the serotonergic and noradrenergic systems appear to provide the most analgesia. Thus, the tricyclic antidepressants (TCAs), which block the reuptake of both serotonin and norepinephrine, are generally much more effective as analgesics than SSRIs such as fluoxetine, paroxetine, sertraline, and citalopram.10 Moreover, when TCAs are administered to patients who are also taking opioids, they appear to bolster the analgesic effect of the opioids. Of the new antidepressants, venlafaxine-which has a mechanism of action similar to that of the TCAs-appears to be most effective for pain.11
How antidepressants effect analgesia is unclear. Among the suggested mechanisms of action are:
The analgesic effect of antidepressants seems to be separate from their antidepressant effect; thus, patients with chronic pain do not need to be depressed in order to benefit from the analgesia these agents provide; in fact, they have no psychiatric effect on patients who are not depressed.
All the TCAs appear to be equally analgesic. Although amitriptyline is commonly thought to be either the only TCA that provides analgesia or the TCA that provides the most analgesia, neither claim is substantiated. Amitriptyline may have been considered most beneficial because of its strong antihistaminic effect, which makes it the most sedating of the TCAs. Many patients with chronic pain have difficulty in sleeping and so are helped by this sedating effect. However, patients may find amitriptyline too sedating. In addition, this agent has the strongest anticholinergic effects of the TCAs; it can cause constipation and urinary retention. Other TCAs, such as desipramine and nortriptyline, have more benign side-effect profiles.
Because venlafaxine does not have the anticholinergic effects of the TCAs or affect cardiac functioning as TCAs can, this agent can be a useful alternative. I prescribe the extended-release form of venlafaxine.
To achieve sufficient analgesia, 100 to 150 mg/d of amitriptyline, an equivalent dosage of another TCA, or 150 to 300 mg/d of extended-release venlafaxine is required in most patients.
Which anticonvulsants provide analgesia?
7Most anticonvulsants appear to provide analgesia and are especially effective for neuropathic pain.12,13 The only anticonvulsant approved by the FDA for the management of pain is gabapentin, which is indicated for postherpetic neuralgia. However, the literature indicates that other new anticonvulsants, including lamotrigine and oxcarbazepine, can also provide significant analgesia.14Because the new anticonvulsants have more benign side-effect profiles, they have generally replaced the older anticonvulsants (such as phenytoin, carbamazepine, and valproate sodium) for use in pain management. There is one notable exception: for reasons that are still unknown, trigeminal neuralgia usually responds better to carbamazepine than to any other medication.
How anticonvulsants exert their analgesic effect is unclear. It is thought that neuropathic pain may be to some degree a result of destabilization of the neuronal membranes and that anticonvulsants restabilize the membranes by blocking the calcium and sodium channels. Some of the analgesic properties of gabapentin may be related to increases in the synthesis and release of gamma;-aminobutyric acid in the brain caused by this agent.
Do the COX-2 inhibitors provide better analgesia than the older, nonspecific NSAIDs?
8All the NSAIDs, including the cyclooxygenase (COX)-2 inhibitors, are equally analgesic.15 The only advantage to the COX-2 inhibitors is their more benign side-effect profile-especially with regard to GI toxicity and effects on platelet function. Thus, the COX-2 inhibitors are better choices for patients in whom NSAIDs are indicated but who are at risk for GI or renal problems or who are being treated with anticoagulants. However, if there are no contraindications to nonspecific NSAIDs, consider using these far less expensive agents. In addition, the old-er NSAIDs may provide prophylaxis against myocardial infarction.16
With both the older NSAIDs and the COX-2 inhibitors, it is difficult to predict which agent will be most beneficial in an individual patient. Therefore, it is worth trying all of those currently available in the class (for example, trying all 3 COX-2 inhibitors-celecoxib, rofecoxib, and valdecoxib) before deciding that a patient is not benefiting from this class of medications.
Are there any other medications that are helpful in the management of chronic pain?
9The lidocaine patch is useful in the treatment of localized pain. Like gabapentin, it has been FDA-approved for the management of postherpetic neuralgia; however, studies indicate that it can also provide significant relief for other types of pain, including low back pain.17I have used lidocaine patches in a variety of neuropathic pain syndromes, including diabetic neuropathy and complex regional pain syndrome (reflex sympathetic dystrophy); I have also found them to be effective in musculoskeletal pain in some patients. Lidocaine patches are left on for 12 hours per day; up to 3 patches can be applied at a time. This medication has a very benign side-effect profile because the analgesic effect is local rather than central. Thus, it is an especially good choice for patients who may have difficulty in tolerating other analgesics.
Capsaicin, a topical medication derived from chili peppers, is useful in the treatment of osteoarthritic pain, localized musculoskeletal pain, and neuropathic pain. Although it usually feels warm when applied, capsaicin's analgesic effect is not a result of the counterstimulation associated with some other topical agents. Its effect has primarily been viewed as secondary to the depletion of peripheral substance P, a neuropeptide involved in the transmission of pain; however, it may actually be the result of a neurotoxic effect on nociceptors.
Capsaicin is available over the counter in topical cream preparations in 0.025% and 0.075% strengths and in a patch with a concentration of 0.9%. I generally recommend the cream rather than the patch because the former is less expensive. Side effects do not appear to be dose-related; how-ever, the higher concentrations may produce a stronger burning sensation. Thus, I recommend starting with the 0.075% preparation. Capsaicin is usually applied 3 or 4 times a day. In my experience, the lidocaine patch tends to be more effective than capsaicin.
One class of medications that are often used inappropriately in chronic pain are the benzodiazepines. Benzodiazepines are generally contraindicated in the treatment of chronic pain-for several reasons:
The 2 settings in which benzodiazepines are most often used in patients with chronic pain are insomnia and spasm.18 Other medications are superior choices for these problems. Insomnia can be better treated with either a sedating antidepressant or with medications specifically formulated for insomnia (for example, zolpidem or zaleplon); spasm is better treated with cyclobenzaprine.
What nonpharmacologic modalities are useful for pain management?
Among the most commonly used are physical therapy and occupational therapy. Patients with chronic pain are often in poor physical condition because the pain impedes their ability to exercise, and the resultant inactivity can, in turn, exacerbate the pain. Physical therapy can frequently improve conditioning and teach patients better body mechanics. Occupational therapy can improve patients' performance of activities of daily living.
Psychotherapeutic techniques can also be beneficial. Many patients with chronic pain have comorbid depression, which may respond to psychotherapy. Therapies that focus on the pain most notably relaxation techniques and biofeedback-can also be helpful.
Acupuncture can also provide analgesia in a variety of pain conditions.19,20Although the pain relief produced by acupuncture is often dismissed as a placebo effect, acupuncture appears to increase the release of endorphins and the bioavailability of serotonin and norepinephrine. Acupuncture has virtually no adverse effects when it is performed by a trained professional and disposable needles are used.
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