by Nicole Berardoni M.D., Tory McJunkin M.D., and Paul Lynch M.D.
Though it is universal, pain is so complex and subjective that it is difficult to comprehend and treat. When a patient has a chronic pain condition, several pharmacologic treatment modalities exist to address the pain. In choosing a medication for pain control, physicians must first correctly diagnose the type of pain a patient is experiencing. Chronic pain may be the result of inflammation or injury to somatic or visceral tissue, termed nociceptive pain. Chronic pain may also be the result of injury or damage to the nerve itself, termed neuropathic pain. Nociceptive pain is most commonly treated with anti-inflammatory and analgesic medications, such as non-steroidal anti-inflammatory drugs (NSAIDS) and opioids. Neuropathic pain, however, is treated differently using medications that act on neurotransmitters and excitable nerves (e.g., antidepressants, anticonvulsant agents). The following categories contain the most commonly prescribed and most well-documented agents for the treatment of both nociceptive and neuropathic chronic pain.
Medication Management – Nociceptive Pain Medications
Nociceptive pain results from tissue damage. Injury to a specific area occurs, which causes intact neurons to report damage to the brain, and pain is experienced. Nociceptive pain can be subdivided into somatic and visceral (gut) pain. Nociceptive pain can be a sharp sensation, although other times it can be dull or aching. There may be radiation of the pain, especially visceral pain, but it will not be in a direct nerve distribution. For example, gallbladder pain can radiate to the scapula. Nociceptive pain is generally responsive to and first treated with non-steroidal anti-inflammatory drugs (NSAIDs), followed with opioids for more severe or refractory pain. Conditions associated with inflammation, bone pain, and joint disease are particularly responsive to NSAIDs. The following categories comprise the most commonly used medications for nociceptive pain.
Medication Management – Acetaminophen (Tylenol)
Acetaminophen is an over-the-counter medication used to treat pain and fever. Acetaminophen works on the parts of the brain that receive the “pain messages,” but it does not have the anti-inflammatory effects of the NSAIDs listed below. Often, however, in cases of chronic pain there is no inflammation at the site of the pain, and thus Tylenol may be an appropriate treatment choice. Tylenol is a safe medication when used appropriately, but can be very dangerous when used inappropriately. The risk of liver or kidney damage is significant when more than the recommended dose of Tylenol is used. If you have liver disease, acetaminophen should only be consumed under your doctor’s supervision. Acetaminophen is often combined with other pain medications to cause an additive effect.
Medication Management – NSAIDs
These are the non-steroidal anti-inflammatory drugs (NSAIDs), and many are available over-the-counter without a prescription. Included in this category are aspirin (Bayer), ibuprofen (Advil, Motrin), ketoprofen (Orudis KT), and naproxen sodium (Aleve). These medications relieve pain by reducing the production of prostaglandins, which are hormone-like substances that cause pain and inflammation. Therefore, NSAIDs can be extremely effective at reducing inflammation and calming swelling and irritation. NSAIDs are most beneficial in cases of acute pain, or flare-ups in patients with chronic pain. In general, these should not be used on a daily basis for the treatment of chronic pain. When used on a daily basis for a period of several years, there is a risk of damage to the kidneys that can be significant. Furthermore, there is a well-known risk of gastric ulcer formation with NSAIDs. While the newer, COX-2 inhibitors (Celebrex, Vioxx) were designed to avoid this complication, caution should still be used if there is a risk of ulcers or GI bleeding.
Medication Management – COX2 Inhibitors
Recently, a new class of NSAIDs has become available, the COX2 inhibitors. Currently available in this class is celecoxib (Celebrex). Selective blockade of cyclooxygenase permits analgesia and an anti-inflammatory effect while minimizing the risk of GI toxicity and bleeding. The COX2 inhibitors have been shown to be as equally effective as other NSAIDS, but do not show evidence of greater analgesia. The COX2 inhibitors are considerably more expensive than other over-the-counter NSAIDS. However, if an NSAID is truly needed and there is concern of GI bleeding, the total cost may be lowered by using one of these agents rather than adding a relatively expensive prophylactic drug such as misoprostol or a pump-inhibitor to counteract the side effects of NSAIDs. Other COX-2 inhibitors including rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market due to potential cardiovascular side effects.
Medication Management – Opioids
When treating chronic pain, narcotic opioids should be considered if pain cannot be otherwise controlled. Although these medications can be dangerous and addicting, they can also be effective when used appropriately. An opioid is a chemical substance that has a morphine-like action in the body. The term opioid is derived from opium, which is an extract from the poppy plant. These agents have been available for centuries to relieve pain.
Opioids work by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract. The receptors in these two organ systems mediate both the beneficial effects and the undesirable side effects.
All of the opioids have similar clinical effects that vary from one another in potency, speed of onset, and duration of action. Both short-acting and long-acting formulations are available, as some opioids are used around-the-clock while others are used as needed for breakthrough pain. One common mistake when treating chronic pain with opioid medications is using the short-acting types of medication (e.g. Percocet, Morphine, Vicodin, etc.). While these medications are useful for acute pain, they are also associated with sedating and euphoric side effects. The short-acting nature of these medications encourages overuse and the development of tolerance. Long-acting opioids may have fewer cognitive side effects and better control of chronic pain.
Although no adequate long-term studies have shown their effectiveness in the treatment of chronic nonmalignant pain, and they are not approved for this use, opioids are often used for this type of pain management. Side effects may include GI upset, nausea, disturbed sleep, constipation, and addiction. Studies show about 5-15% of chronic pain patients using narcotic pain medications develop dependence.
The following is a comprehensive listing of the broad classes of narcotics:
- Natural opioids: Alkaloids contained in the resin of the opium poppy (morphine, codeine, thebaine, and oripavine)
- Semi-synthetic opioids: From the natural opioids (hydromorphone, hydrocodone, oxycodone, and heroin)
- Fully-synthetic opioids: Produced synthetically (fentanyl, pethidine, methadone, and propoxyphene)
- Endogenous opioid peptides: Produced naturally in the body (endorphins, enkephalins, dynorphins, and endomorphins)
Medication Management – Atypical Opioids
Tramadol (Ultram) is an atypical opioid that is a centrally acting analgesic, used for treating moderate to severe pain. It is a synthetic agent and analogue of codeine and appears to have actions on the GABAergic, noradrenergic, and serotonergic systems. Unlike most other opioids, Tramadol is not considered a controlled substance in many countries (including the U.S.). An extended-release formula is available to treat moderate to severe chronic pain when treatment is needed around the clock.
Medication Management – The Opioid Controversy
Considerable debate exists about the use of opioids for treatment of chronic pain of non-cancer origin. Many physicians feel that opioids can play an important role in the treatment of all types of chronic pain, including non-cancer pain. Others caution against the widespread use of opioids, noting problems with tolerance, loss of benefit with time, and escalating usage with decreasing function in many individuals. The use of opioids (or for that matter any treatment) makes sense when the benefits outweigh the risks and negative side effects.
Benefit is suggested when there is a significant increase in the person’s level of functioning, when there is a reduction or elimination of pain complaints, when there is a more positive hopeful attitude, and when side effects are minimal or controllable. The dilemma with the long-term use of opioids is that while there is a role for opioids in chronic, non-cancer pain, it is well-known that prolonged use of opioids may result in problems including tolerance, hyperalgesia (abnormal pain sensitivity), hormonal effects (decreased testosterone levels, decreased libido and sex drive, and irregular menses), depression, and suppression of the immune system. While opioid treatment may be prescribed to reduce pain and improve function, the treatment may actually result at times in just the opposite.
Medication Management – Neuropathic Medications
Neuropathic pain is associated with injury to the nerve. Often this type of pain is characterized by burning sensations, increased sensitivity, or shooting sensations over the affected area. Patients often describe this type of pain as severe, sharp, lancinating, lightening-like, stabbing, burning, numbness, tingling, or weakness. It is important to understand neuropathic pain because it has very different treatment options from other types of pain. Remedies for nociceptive pain, such as NSAIDs and opioids, do not work as well for neuropathic pain, which is only marginally affected by opioids and anti-inflammatories. Neuropathic pain seems to respond best to membrane-stabilizing medications. These medications are made up of the anti-convulsants, tricyclic antidepressants, and select antidepressant medications. These medications act by blocking the brain’s neurotransmitters. The antidepressant medications also have beneficial effects of improved mood, decreased anxiety, and improved sleep cycle. These medications are not addictive and, when appropriately managed, have few side effects.
Medication Management – Anticonvulsants
The anticonvulsant medications can be divided into first- or second-generation agents. The second-generation medications are generally better tolerated and have fewer central nervous system (CNS) side effects than the first-generation agents.
Of the first-generation agents, carbamazepine (Tegretol) has been effective in the treatment of trigeminal neuralgia. Evidence has also shown moderate efficacy in the treatment of postherpetic neuralgia and diabetic neuropathy. Carbamazepine’s main side effect is sedation. Patients treated with it should also have complete blood counts (CBCs) and liver function tests (LFTs) monitored, as blood dyscrasias and liver abnormalities can occur with the medication. These generally resolve with discontinuation of the drug.
The second-generation antiepileptic agents have shown the best documented resolution of neuropathic pain, although the mechanism of action of these drugs remains unknown. Gabapentin (Neurontin) is the first line agent in the treatment of painful diabetic neuropathy and postherpetic neuralgia. Many physicians begin treatment with this agent, mostly because it has been well tolerated, even at high doses. In fact, some evidence shows an anti-anxiolytic effect, and therefore it may be helpful for anxious patients. Unlike carbamazepine, it lacks significant interactions with other drugs. Patients may experience nausea, especially with rapidly increasing doses, or dizziness with higher doses.
The FDA recently approved the use of the new anticonvulsant drug, pregabalin (Lyrica), for the treatment of neuropathic pain. It was designed as a more potent successor to gabapentin. Lyrica has also been shown to be effective in the treatment of diabetic neuropathy and postherpetic neuralgia. This drug can be given less frequently than gabapentin (twice daily versus three times daily), although it is a Schedule V controlled substance. The FDA also recently approved the use of Lyrica for the treatment of fibromyalgia. It is currently the only FDA-approved drug for the treatment of pain associated with fibromyalgia.
Medication Management – Antidepressants
Chronic pain often is associated with emotional havoc, which interferes with the improvement of pain. Antidepressant medications have been show to have success with the treatment of chronic pain. In addition, these medications have the added benefit of improved mood, improved sleep cycles, and decreased anxiety. Antidepressants are drugs that can treat pain or emotional conditions by adjusting levels of neurotransmitters (natural chemicals) in the brain. They can increase the availability of the body’s signals for well-being and relaxation, enabling pain control for people with chronic pain conditions that do not completely respond to the usual treatments.
Although several categories of antidepressants exist, the tricyclic antidepressants are most commonly used for the treatment of chronic pain. In low doses, these medicines are effective at relieving pain, while higher doses have a more typical antidepressant effect. Amitriptyline (Elavil) is the antidepressant most commonly prescribed from this group, simply because it has been studied the most thoroughly. Other tricyclic antidepressants used for pain control include: Imipramine (Tofranil), Nortriptyline (Pamelor), and Desipramine (Norpramin).
Tricyclic antidepressants seem to work best for the burning or searing pain common after nerve damage, which sometimes occurs with diabetes, shingles, or stroke. These drugs are also effective in some people for fibromyalgia or as a preventative medication for migraines. Tricyclic antidepressants don’t cause dependence or addiction, and they’re safe to take for long periods of time. But they can make you drowsy. In addition, these drugs may cause dry mouth, constipation, weight gain, difficulty with urination, and changes in blood pressure. To reduce or prevent side effects, your doctor will likely start you at a low dose and slowly increase the amount. Most people are able to take tricyclic antidepressants, particularly in low doses, with only mild side effects. The doses that are effective for pain are typically lower than the doses used for depression.
Two newer forms of antidepressants — selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) — have fewer side effects than tricyclic antidepressants and are sometimes used to treat chronic pain. SSRIs include such drugs as paroxetine (Paxil) and fluoxetine (Prozac). People who have chronic pain may feel better while taking SSRIs, but this effect is believed to result more from the easing of accompanying depressive symptoms rather than from actual pain relief. Drugs such as venlafaxine (Effexor) and duloxetine (Cymbalta) are SNRIs, which appear to be more effective than SSRIs at pain control, particularly neuropathic pain caused by damaged nerves. Cymbalta has an FDA indication for treating diabetic peripheral neuropathy. SSRIs and SNRIs are known to have fewer side effects than the tricyclic antidepressants, and therefore, may be better treatment options for chronic neuropathic pain.
Medication Management – Conclusion
This is an introduction to the medication management of chronic nonmalignant pain. One of the most useful ways to conquer pain is to understand it, and hopefully this will merely be the first of many resources you turn to. Furthermore, there are many treatment modalities besides medications which may be very helpful for your chronic pain management.
- Ballantyne JC (2006). “Opioids for chronic non-terminal pain”. South. Med. J. 99 (11): 1245-55. PMID 17195420
- Fields HL, Martin JB (2005). Pain: Pathophysiology and management. In DL Kasper et al., eds., Harrison’s Principles of Internal Medicine, 16th ed., vol. 1, pp. 71–76. New York: McGraw-Hill
- Katz, WA “The Needs of a Patient in Pain” Amer. J. Med. 1998. 105(1B) Pages 2S-7S.
- Marcus, DA “Treatment of Nonmalignant Chronic Pain” Amer. Family Physician. 2000. 61(5) Pages 1331-8.
- Munir MA, Enany N, Zhang JM. “Non-opioid analgesics”. Med. Clin. North Am. 2007. 91 (1): 97-111. PMID 17164106.