Let us review the classes of common analgesics before getting into a more in depth discussion of routes of therapy and dosing strategies for opioids.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
NSAIDs are a mainstay in the management of mild to moderate nociceptive pain. As mentioned above, they are particularly useful in inflammatory states and in pain involving the musculoskeletal system.10 It is beyond the scope of this book to discuss the large number of NSAIDs available today. Rather, some guidelines for choosing and using them are offered.
- Consider drug half-life and frequency of administration. Short-acting agents such as ibuprofen may be preferable for pain that arises intermittently and is of short duration. Such agents can be given on an as needed basis. For patients with chronic pain that requires round-the-clock analgesia, a longer-acting agent such as naproxen, which may allow more convenient dosing, may result in better patient compliance and improved analgesia.
- It is a mistake to consider NSAIDs as necessarily less toxic than opioids. NSAIDs may cause upper intestinal symptoms such as heartburn, nausea, or vomiting in 10% to 20% of patients. Significant upper GI bleeding from either gastritis or duodenal ulceration can occur, as can nephrotoxicity. Bronchospasm may be precipitated in sensitive asthmatics, as with aspirin. NSAIDs can cause altered mental status, especially in the elderly and frail. Most NSAIDs inhibit platelet aggregation. This is particularly a risk in patients who receive anticoagulants and in patients with thrombocytopenia.
- For some patients NSAIDs may be as effective or more effective than are opioids in relieving pain. In such cases it may be a mistake to withhold this class of medication for fear of some of these side effects. Rather, additional steps may be necessary to minimize the risk. Misoprostol, a prostaglandin E1 analog, can significantly reduce the risk of gastritis and gastric ulceration due to NSAIDs. Misoprostol is also effective against duodenal peptic ulceration. H2 blockers, such as ranitidine, have been found to reduce the risk of duodenal ulcers for patients treated with NSAIDs. Standard doses of H2 blockers such as famotidine 20 mg BID do not protect against NSAID-related gastric ulcers. However, one study with higher dose famotidine, 40 mg BID, did show a protective effect. Identification and eradication of H. pylori infection may lessen the risk of bleeding with NSAIDs in those infected for both duodenal and gastric ulcers. When there is concern over renal function, careful monitoring of blood chemistries may allow early detection of adverse effects. If deterioration in renal function is detected, discontinuation of the NSAID usually results in a gradual return to baseline function. Use of COX2 inhibitors (see below) may also help minimize risk.
Recently, a new class of NSAIDs has become available, the COX2 inhibitors.12 Selective blockade of cyclooxygenase permits analgesia and an anti-inflammatory effect while minimizing the risk of GI toxicity and bleeding. Although experience in the use of these drugs in palliative care is limited, the following should be helpful in considering when to use one of these agents.
- They are relatively expensive. This makes them considerably more expensive than naproxen, for example. However, in absolute terms, if an NSAID is truly indicated and significant contraindications exist for standard NSAIDs, the difference in price may be worth it.
- They appear to be equi-efficacious with other NSAIDs but with no evidence of superior analgesia.
- Evidence is strong that the risk of GI bleeding is significantly reduced with these agents.13 When an NSAID is truly needed and there is concern about GI bleeding, the total cost may be lowered by using one of these agents rather than by adding a relatively expensive prophylactic drug such as misoprostol or a pump-inhibitor.
- Evidence is strong that platelet aggregation is not inhibited by these agents. Thus, in patients with thrombocytopenia, defective platelets (uremia), and bleeding tendencies these drugs may offer a strong advantage.
Opioids – A Misunderstood Class of Drugs
Many misconceptions exist relative to the use of opioids. These misunderstandings have resulted in global underuse of these medications for pain relief. It is a mistake to extrapolate from the effects of opioids on addicts to the effects of opioids on patients in pain. Opioids used for pain relief act very differently on the body and mind than do opioids used by people not in pain. Most of the horrors observed in addicts do not occur in patients who take opioids for pain relief. The presence of pain itself changes the effect of opioids. When we administer opioids for pain relief, we do so considering the opioid to be an antidote to the poison of pain. Many are not aware that pain reciprocally acts, in part, as an antidote to certain of the toxic effects of opioids. Ideally, the effects of pain and opioids cancel each other out, allowing pain relief with minimal toxicity.
Pain can serve as a partial antidote to certain opioid side effects – euphoria, sedation, and respiratory depression.
Pain also seems to block much of the euphoric effect of opioids. Contrary to popular thinking, the risk of turning a nonaddict into an addict when treating pain is very, very small to nonexistent. In one review by Porter, 11,882 patients without a prior history of addiction who were treated for pain with opioids were followed to determine how many developed addictive behavior. Only four did so.14 A more recent study reviewed statistics on the medical use of opioids and the incidence of opioid abuse from 1990 to 1996 in the United States. It found that while medical use of opioids (except for meperidine) had increased dramatically over that period of time (morphine use up 59%), this trend was not paralleled by increased opioid abuse. It concluded, “The trend of increasing medical use of opioid analgesics to treat pain does not appear to contribute to increases in the health consequences of opioid analgesic abuse. Physical dependence does occur with repeated dosing. However, such dependence does not result in craving for the drug, associated with deleterious life consequences (a definition of addiction). It is notable that many drugs cause similar dependence without addiction – meaning that sudden discontinuation of the drug results in adverse physiological effects. Beta blockers, clonidine, and steroids, among others, can result in physical dependence.
If pain is skillfully treated with opioids, adverse complications such as respiratory depression and significant sedation rarely occur. No good evidence base exists for the common belief that the proper use of opioids (compared to the use of opioids by addicts) in the treatment of pain hastens the chance of death. Mild sedation and nausea may occur with initiation of opioid therapy or with subsequent increases in dosing. These side effects relate more to increases in opioid dosing and serum levels than to the absolute amounts of opioid administered. They usually subside after steady state levels are achieved – usually in a day or two.
While sedation and nausea tend to resolve over time as steady serum levels are obtained, such is not the case with constipation. As a rule, patients receiving chronic opioid therapy require continuous laxative therapy. This need for laxatives should be anticipated at the outset of therapy and not when constipation becomes a problem, as it almost inevitably does. Constipation is caused by opioids binding mu receptors in the intestinal track. Patients on very high doses of opioids do not necessarily require higher laxative doses to compensate than do those on lower doses. Orally administered opioids may result in somewhat more severe constipation than does transdermally administered fentanyl, perhaps because of more concentrated mucosal exposure.
Side effects related primarily to rising serum opioid levels are sedation, nausea and vomiting, and respiratory depression. Effects related primarily to steady state opioid levels are pain and dyspnea relief and constipation.
Many physicians fail to prescribe opioids when indicated because of fear that they may be criticized or, worse, have their licenses revoked for improperly prescribing narcotics. However, with proper documentation of relevant history, physical exam, diagnosis, indication for therapy, and response to therapy, there is little to fear. Triplicate prescriptions, where still required, and local institutional policies regarding order and prescription renewal are significant barriers to proper opioid use. However, these should not limit the use of opioids when they are truly indicated.
Finally, some may be reluctant to use opioids, as they may wish to save the “big guns” for later. While tolerance to opioids does exist, it is not a major problem and usually occurs in patients who require large doses of opioids. For most patients tolerance is not a problem at all. Many patients are successfully maintained on a steady dose of opioids for months to years. When patients complain of increased pain on opioids, it usually reflects worsening underlying disease. Equally important, there is no absolute dose ceiling for opioids (unlike acetaminophen, aspirin, and NSAIDs). Some patients may require and do quite well on the equivalent of more than 100 mgs of IV morphine an hour.