Chronic Musculoskeletal Pain: Rational Use of Opioid Analgesics, Part 1

ABSTRACT: Opioid analgesics are used routinely in managing acute musculoskeletal pain. However, physicians often hesitate to use them for chronic pain, such as that seen in rheumatoid arthritis, osteoarthritis, osteoporosis, and low back pain. Starting the patient at a low dose and progressively titrating upward for pain relief minimizes the adverse effects. The fear that prescribing opioid analgesics for chronic pain will engender addiction is not supported by experience.

Throughout history, various forms of morphine have been the most effective medications in relieving pain. Opioid analgesics—the natural, semisynthetic, and synthetic derivatives of morphine—are used routinely in the management of acute musculoskeletal pain. However, myths and misunderstandings about these drugs often prevent primary care physicians from prescribing them for chronic pain, such as that seen in common musculoskeletal conditions (eg, rheumatoid arthritis, osteoarthritis, osteoporosis, and low back pain). Although pain is one of the most common symptoms that bring patients to the physician's office, those with chronic musculoskeletal or other noncancer pain all too often are undertreated.

In many cases, the use of opioid analgesics for patients with chronic musculoskeletal pain is a legitimate treatment approach, and it is gaining acceptance in the medical community. Although some reports question the efficacy of long-term use of opioid analgesics in improving function,¹ several randomized controlled trials of these agents showed at least a 30% reduction in pain.² Although these medications are effective, physicians tend to underuse them because they lack knowledge about them and about addiction. They also fear regulatory scrutiny.

In part 1 of this 2-part article, I review the properties and adverse effects of opioid analgesics and describe the differences between physical dependency and addiction. In part 2 in a coming issue, I will discuss how to assess patients who have chronic pain, determine the safety and appropriateness of treating them with these agents, and monitor them on a regular basis.

EFFECTS AND ADVERSE EFFECTS

Opioid analgesics exert their effects by binding to μ, κ, and δ receptors in the CNS (brain and spinal cord), the GI tract and, to a lesser extent, the peripheral tissues. They counteract pain signals ascending to the brain. Pain relief is their desired effect, but they also have adverse effects (eg, nausea, sedation, and constipation).

Starting treatment at a low dose and progressively titrating upward for pain relief minimizes the adverse effects while permitting development of tolerance (the need for an increased dose to achieve the same adverse effect or a diminished effect with the same dose) to the nauseating and sedating effects. Tolerance to nausea and sedation (and its extreme, respiratory depression) is desirable, but there is no tolerance to the constipating effect of opioid analgesics. Therefore, it is important for the patient to maintain a bowel regimen (stool softener, bowel stimulant, fluids, and activity) for as long as an opioid analgesic is being taken.

Tolerance to the pain-relieving effects of opioid analgesics is uncommon. Once titrated to an effective pain-relieving dose, most patients continue taking the same or a similar dose for long periods.^3-5 Pain specialist Russell Portenoy, MD,⁶ wrote, "Contrary to conventional thinking, the development of analgesic tolerance appears to be a rare cause of failure of long-term opioid therapy."

Although there is some evidence to indicate that long-term exposure to high doses of opioid analgesics results in hyperalgesia (increased pain sensitivity),⁷ this is rarely of clinical significance. Most often, a request for an increased dose reflects increased physical activity, a worsening physical problem, or deterioration in the patient's psychological status (eg, depression).

An often unappreciated adverse effect of long-term opioid analgesic use is lowered sex hormone levels in men. In those who are taking significant doses of opioid analgesics long-term, subnormal testosterone levels are the rule rather than the exception.⁸

Plan on checking total and free testosterone levels in all men who are taking moderate to high doses of opioid analgesics. Many will need testosterone replacement, preferably with patches or transdermal preparations. It is wise to also monitor their prostate-specific antigen levels.

I recommend checking testosterone levels even in asymptomatic patients. Untreated hypotestosteronism can lead to osteoporosis in men, as well as decreased muscle strength.

Some patients taking morphine experience itching. Morphine is more likely than other opioid analgesics to cause histamine release and pruritus. If antihistamines do not provide enough relief, switching to another opioid analgesic may be the answer.

There is no accepted upper limit of safety for opioid analgesics. Because of genetic differences and varying pathology, there are enormous differences in patients in the amount of opioid analgesics they need for adequate pain relief. Historically, some patients with cancer have required grams of morphine. For many patients, however, 5 mg of hydrocodone( (in Vicodin or Lorcet) provides adequate pain relief.

As long as the dose is started low and increased gradually, large doses may be taken and are limited only by adverse effects. Unlike acetaminophen, aspirin(, and many other drugs, opioid analgesics do not have any specific organ toxicity. Thus, the right dose is the one that provides adequate pain relief without unacceptable adverse effects.

Typically, it takes 3 to 7 days for the body to overcome sedation produced by opioid analgesics. Thus, it is wise for patients to avoid driving when they begin to take these drugs and when they increase the dose. Once patients are taking a stable dose and feel alert, generally it is safe for them to drive because they have adequate psychomotor functioning.^9-11 Of course, it is wise to avoid using alcohol and benzodiazepines before driving, because they are likely to increase any sedative effects of opioid analgesics.

Opioid analgesics are significantly safer than NSAIDs; they are not associated with upper GI bleeding or renal toxicity. This may be particularly important in older patients who are at risk for the GI and renal toxicity of NSAIDs.

Continued on next page

PHYSICAL DEPENDENCY VERSUS ADDICTION

Many physicians and laypersons believe that anyone who is taking opioid analgesics long-term becomes addicted. This misunderstanding results from confusion with the concepts of physical dependency and addiction.

Physical dependency. This is a form of physiological adaptation to the continuous presence of certain drugs in the body. Abrupt discontinuation of the drug after the body has become accustomed to it results in a predictable withdrawal syndrome. For opioid analgesics, this may include anxiety, irritability, goose bumps, salivation, lacrimation, rhinorrhea, diaphoresis, nausea and vomiting, abdominal cramps, and insomnia.

Withdrawal from morphine begins at 6 to 12 hours after last use and peaks at 1 to 3 days. The symptoms associated with longer-acting opioids, such as methadone, have a slower onset and are less severe than those with shorter-acting drugs, such as morphine and hydromorphone(. Withdrawal symptoms may be avoided by tapering the drug over days.

Patients who take opioid analgesics for more than a few days should be considered physically dependent. The patient should be cautioned to avoid stopping the opioid suddenly because withdrawal symptoms may appear. Even if pain stops totally, the medication should be tapered. Opioid withdrawal is not dangerous, but it can be very uncomfortable.

A patient's physical dependence on an opioid analgesic is a physiological state in which abrupt cessation of it or administration of an opioid antagonist results in a withdrawal syndrome, according to the American Society of Addiction Medicine.¹² It is expected in all persons in the presence of continuous use of opioids for therapeutic or nontherapeutic purposes and does not, in and of itself, imply addiction.

Corticosteroids are another class of drugs that produce physical dependency. The corollary, known by all physicians, is that when corticosteroids are stopped after ongoing use, they should be tapered rather than stopped abruptly. The same is true of opioid analgesics.

Addiction. This is a psychological and behavioral disorder characterized by the presence of all 3 of the following:

As an addiction advances, the person's life becomes progressively more constricted. The addiction becomes the addict's top priority, and relationships with family and friends suffer. The addict's mental interior becomes filled with preoccupation about the drug. Other activities are given up. Life revolves around obtaining and using the drug. This constriction distinguishes use of a drug by an addict from its appropriate use by a patient who has chronic pain.

In the medical setting, a patient who is addicted to drugs will show some of the following signs:

Clinicians who are uncomfortable prescribing opioid analgesics probably have patients who keep requesting more medication and seem preoccupied with the quantity being prescribed. These patients often are stigmatized with the label of "drug seeker." The real problem may be that the pain management is inadequate. Once a sufficient dose of opioid analgesic is prescribed, this phenomenon—termed "pseudoaddiction"— vanishes.

Does prescribing opioid analgesics for pain lead to addiction? The fear that prescribing them for chronic pain will engender iatrogenic addiction is not supported by experience. Addiction to opioid analgesics in patients who do not have a history of addiction rarely results from longterm opioid treatment for pain.^3,14

CLINICAL HIGHLIGHTS

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	Typically, it takes 3 to 7 days for the body to overcome sedation produced by opioid analgesics. Thus, it is wise for patients to avoid driving when they begin to take these drugs and when they increase the dose.
	There is no tolerance to the constipating effect of opioid analgesics. Therefore, it is important for the patient to maintain a bowel regimen (stool softener, bowel stimulant, fluids, and activity) for as long as an opioid analgesic is being taken.
	As long as the dose is started low and increased gradually, large doses may be taken and are limited only by adverse effects.
	An often unappreciated adverse effect of long-term opioid analgesic use is lowered sex hormone levels in men. Plan on checking total and free testosterone levels in all men who are taking moderate to high doses of opioid analgesics.
	The fear that prescribing opioid analgesics for chronic pain will engender iatrogenic addiction is not supported by experience. Addiction to opioid analgesics in patients who do not have a history of addiction rarely results from long-term opioid treatment for pain.

Screening tests now available to help determine a patient's risk of abusing opioids include the Opioid Risk Tool (ORT)¹⁵ and the Screener and Opioid Assessment for Pain Patients (SOAPP),¹⁶ which has 14- and 24-item versions. These tools should be used to gain a sense of which patients may need additional structure as part of their treatment plan rather than to exclude specific patients from consideration for long-term opioid treatment.

Even patients who have a previous history of addiction need not automatically be excluded from opioid analgesic treatment for chronic pain. Experience has demonstrated that known addicts may benefit from the carefully supervised, judicious use of opioid analgesics for pain resulting from cancer, surgery, or recurrent painful illnesses.¹⁷ When contemplating prescribing opioid analgesics for a patient with an addiction history, however, primary care physicians are advised to consult with a pain or addiction medicine specialist.

For such patients, careful supervision is the key. This includes a contract outlining the physician's expectations of the patient, provisions made for random urine screens, and increased attendance at 12-step selfhelp meetings.^18,19

Recovering alcoholics are less likely to relapse than are patients who once were addicted to opioid analgesics.²⁰ Prescribing them for the latter group should be considered only as a last resort—when every other approach has failed and with the participation of an addiction medicine specialist. Patients who are current drug addicts cannot be trusted to manage their opioid pain medications reliably. Therefore, these patients are not candidates for opioid therapy unless they are in a supervised setting with someone else dispensing the medication.