UPDATE ON THE PHARMACOLOGIC MANAGEMENT OF CANCER PAIN

Cancer research has developed and progressed at a rapid and quickening pace in recent years. This progress has taken place in a number of different domains, including clarification of the mechanisms by which the numerous types of cancer grow, metastasize, and die. Knowledge of basic cellular mechanisms of cancer has tremendously assisted in the development of agents for ameliorating, controlling and curing cancer. Despite the impressive achievements of oncology researchers, however, morbidity and mortality due to cancer continue to rise.1 With the rising cancer rates comes an increasing demand to address cancer pain. Just as strides have been made in developing anticancer agents, so too has progress been made in the development of agents to address cancer pain.

Barriers to Appropriate Treatment
Recent development of agents to treat cancer related pain, and new, sophisticated methods of delivery of these agents, have supplemented those already available. As a result, the vast majority of patients experiencing pain related to cancer or its therapies can be effectively managed with relatively easy to use interventions. Cancer patients should be reassured that they need not live with, or in fear of, uncontrolled pain. Nevertheless, a number of barriers to appropriate implementation and use of pain therapies continue to exist. A lack of appropriate knowledge on the part of some healthcare providers, as well as patient and caregiver misconceptions about pain or opioid analgesics, and limitations of healthcare resources, may all contribute to suboptimal pain therapy.

Opioid therapy is the cornerstone of cancer pain management. Yet, resistance to opioid use, while gradually diminishing, remains a significant barrier to effective therapy. Such resistance takes multiple forms. One such form of resistance is reflected in cultural and religious beliefs regarding the experience of pain. Some patients may regard pain as inevitable or even deserved and resent or resist treatment aimed at minimizing pain. Other patients may regard the use of opioids as a last resort, signifying lost hope of recovery, and may reject medication on these grounds.2

More commonly, concern among patients and some healthcare providers about the perceived addictive properties of opioids cause these medications to be underutilized or avoided entirely. This concern is significantly exacerbated by legal and regulatory barriers. Intractable pain treatment acts, enacted by numerous state legislatures have been passed in order to assure patient comfort and appropriate opioid use. The intent of these laws was to also lessen legal concerns by health care providers when appropriately prescribing opioids for pain management. Much of this misdirected concern is based on a confusion between tolerance, physical dependence, and addiction.

Tolerance describes a systemic adaptation to an agent in which the effectiveness of the agent decreases over time when there is no increase in the pain source. This pharmacologic property is not unique to opioids. Tolerance is common with long-term opioid use and is not a sign of dysfunction or drug failure. Tolerance generally occurs in days to weeks after initiation of opioid therapy. A continued need to increase the opioid dosage more likely indicates progression of the disease or source of the pain stimulus rather than tolerance.

Physical dependence is revealed when the agent is abruptly discontinued, when there is a rapid dose reduction, or when an antagonist is administered (such as naloxone, in the case of opioids). The patient, who has almost always used opioids for at least several weeks, manifests a syndrome of withdrawal symptoms. Such symptoms include nausea, vomiting, abdominal cramping, insomnia, diarrhea, diaphoresis, hot flashes, and autonomic dysfunction. Physical dependence on opioids is normal and by no means analogous to addiction. Patients with addiction will also be dependent, but the reverse is not necessarily true. When opioids are no longer needed, many of the symptoms associated with withdrawal may be avoided by a gradual, tapering reduction in analgesic dosage and the judicious use of opioid antagonists.

Addiction to opioids is a distinct neurobiological disorder, comprised of a variety of potentially contributing factors including those of social, genetic, and environmental origin. Addiction behaviors may include a lack of control over use of an opioid, craving for or obsessive preoccupation with an opioid, and compulsive use of the opioid even after the point at which it is doing harm. While addiction to opioids is of significant concern, addiction in chronic pain patients – either cancer or noncancer – occurs relatively infrequently when there are no previous risk factors for addiction.3 In comparison, patient addiction to opioids decreases function while patient usage of opioids to adequately control pain results in enhanced function even if dependence occurs.

The ongoing efforts to contain healthcare costs constitute a further challenge to the appropriate treatment of pain. Many pain specialists have procedure-oriented practices, with resultant increased pain management delegation to primary care providers. If a primary care provider lacks the time, resources, and knowledge to treat pain appropriately, the risk of patients being undertreated for pain increases. Indeed, despite clarification in medical literature of the appropriateness and utility of opioids for chronic pain, inadequate analgesia continues to be a serious problem across the spectrum of demographic groups.4

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Opioid therapy constitutes the primary means of treating persistent cancer pain. For most cancer patients, pain can be treated with an oral opioid alone or in combination with coanalgesics.5 Apart from opioids, several other drug classes have been applied more specifically to cancer pain, including NSAIDs and bisphosphonates. There are circumstances where these drugs will be more effective analgesics or less toxic than opioids. Addressing the entire pharmacologic armamentarium for the treatment of cancer pain in detail is beyond the scope of this article. The focus will instead be confined to a brief description of available cancer pain agents and a more detailed review of several recent advances in analgesic therapy. Of primary importance is the fact that effective anticancer therapy can be extremely beneficial in reducing or eliminating pain secondary to a cancer. This should not preclude analgesic use for the patient in pain, possibly for a short time, even if anticipated effective therapies are to be used.

NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used as analgesics for patients with mild to moderate pain. NSAIDs have relatively limited use for the patient with cancer and severe pain. NSAIDs can cause end organ toxicity which may be exacerbated in the patient with a malignancy who can have metastasis to these organs or suboptimal organ function secondary to co-morbid medical conditions. Chemotherapy or radiation therapy-induced organ toxicities also necessitate caution in the use of NSAIDs. NSAIDs are further limited in their application for more severe cancer pain by their fixed dose ceiling.

Adverse effects of NSAIDs include GI toxicities (e.g. dyspepsia and ulcer formation), liver dysfunction, bleeding resulting from inhibition of platelet aggregation, renal insufficiency, and in rare cases, acute renal failure.6 Not all NSAIDs confer equal risk of adverse effects. Since NSAIDs tend to be relatively similar in analgesic efficacy, selection of an NSAID is usually based upon the cost, convenience in administration, route of administration needed and possible toxicity profile. Opioid analgesics usually do not have a ceiling dose or histopathologic associated organ toxicities and in many cases will be the safer and more effective analgesic.

Clinical trials have suggested that combining an NSAID with an opioid may provide improved analgesia and may also be dose-sparing of the opioid. Most of these studies compare opioid monotherapy versus an opioid with an NSAID. In general, the studies report that an opioid combined with an NSAID is either more effective or equally effective as an opioid alone.7 Such studies are notable for their short duration, however, most of them lasting for only 1 to 7 days.

One study, performed by Mercadante et al, employed a sophisticated study design in order to provide more pragmatic data.8 Forty-seven patients with advanced cancer who were experiencing pain progression after one week of morphine stabilization were randomized into two groups: Group O and Group OK. Group O received continued morphine escalation based on their analgesic needs, while Group OK received the NSAID, ketorolac, in a daily oral dose of 60 mg and also continued morphine dose escalation as needed. The OK group experienced superior analgesia after 1 week (P = 0.005), and from the 1-week point on, morphine escalation occurred at a slower place. Maximum morphine doses were also lower in the OK group. Gastric discomfort occurred at higher rate in the OK group and constipation was higher in the morphine only group. A pharmacoeconomic analysis found that cost differential in the OK compared to morphine-only were negligible.

Bisphosphonates
The standard treatment for metastatic bone disease and pain can include opioids, NSAIDs, and bisphosphonates. Proven bisphosphonate benefit, at this time, is primarily found in the prevention of morbidity from bone metastases in a variety of tumor types. Bisphosphonates can directly effect some metastatic bony sites and at least partially ameliorate bone pain.9 Guidelines provided by the American Society of Clinical Oncology (ASCO) for the use of bisphosphonates in breast cancer do not recommend initiating patients on bisphosphonate therapy in the absence of bony metastasis.10 ASCO further recommends that bisphosphonates not displace standard analgesic treatment and radiation therapy. Bisphosphonates are reported to occasionally improve pain associated with bone metastases. Further study is required in order to clarify their precise role in cancer pain therapy.

Opioids
Opioids for Mild to Moderate Cancer Pain
A number of opioid formulations are available for treatment of mild to moderate cancer pain. One of the better known and long-established opioids is propoxyphene, which is still widely used for many types of mild pain. It is recommended that this drug rarely be used in cancer related pain management. Propoxyphene is a less desirable opioid because of its low potency, extended half-life, and risk of accumulation of norpropoxyphene, a toxic metabolite. Codeine is also of limited value in cancer pain treatment, since it becomes unacceptably toxic at doses over 90-100 mg. It is also relatively impotent and requires metabolism to its active form. Hydrocodone is a morphine-like opioid that is available in combination formulations, most commonly with acetaminophen, but also with aspirin and ibuprofen. While hydrocodone is not itself limited by a dose ceiling, its combination with these agents confers a dose ceiling by association. Nevertheless, hydrocodone formulations, in limited doses, are relatively safe and effective for mild to moderate pain. Oxycodone combinations with aspirin or acetaminophen are frequently used in moderate pain, and the fixed formulations available allow for 10-20 mg oxycodone dosing every four hours.

Tramadol
Tramadol is a synthetic opioid analgesic indicated for use in moderate pain. It is a weak mu opioid agonist with a side effect profile similar to that of most opioids, but with less likelihood of associated dependence, tolerance and addictive potential. Tramadol also possesses mild selective serotonin and norepinephrine reuptake inhibitor properties, and thus has central effects separate from opioid mechanisms. Doses greater than 400 mg per day have been associated with seizures.

Opioids for Severe Cancer Pain
Opioid therapy constitutes the primary means of treating moderate to severe cancer related pain. For most patients, pain can be treated with an oral or transdermal opioids alone or in combination with coanalgesics. Morphine, with its well characterized pharmacology, is the most frequently used opioid for severe pain. This is primarily because it has numerous dosing formulations and is the most geographically available opioid. Hydromorphone, oxycodone, and fentanyl are also commonly used opioids for severe pain in the U.S. and other countries where it is available. Parenteral formulations are available in the U.S. for all of these agents except oxycodone. Parenteral use should be considered primarily for acute pain management, difficult to control pain requiring patient controlled analgesia, and for patients who cannot use an oral or transdermal formulation. Topical opioids also have been used for a variety of local pain issues, but this also is beyond the confines of this article. Agents with long and often unpredictable half-lives, such as methadone and levorphanol, should be prescribed primarily by those experienced in their pharmacokinetic and pharmacodynamic properties. These drugs can be extremely effective for patients whose pain is not controlled with other opioids, but their unique pharmacologic properties make them more challenging to use while avoiding significant toxicity problems. Opioids with mixed agonist-antagonist properties – such as pentazocine, butorphanol, dezocine, and nalbuphine – are also rarely used due to risk of withdrawal syndrome, reverse analgesia, and dose ceiling. Similarly, partial agonists such as buprenorphine, have had a limited role in the treatment of moderate to severe cancer related pain, but new formulations are in development that may result in improved ease of use.

Opioids for Chronic Cancer Pain
Opioids recommended for use in chronic cancer pain include morphine, oxycodone, hydromorphone, and fentanyl. Morphine, hydromorphone and oxycodone are available in both rapid release and extended release oral formulations. The advantage of extended release formulations is that they allow for less frequently administered round-the-clock analgesia and often mitigate against significant serum fluctuations of active or toxic metabolites. Patient adherence to analgesic regimens can be enhanced with less frequent administration. Morphine and hydromorphone are commonly used as parenteral opioids for hospitalized patients, and long-acting formulations of these drugs make switching to oral forms of tolerated parenteral agents easier.

Fentanyl, which is available in transdermal, intravenous, and transmucosal formulations, is most often used for chronic pain in the transdermal formulation. It is approved for use only in the opioid tolerant patient. As with all the opioids, the pharmacokinetics and pharmacodynamics of the active drug, its metabolites, and delivery vehicle should be known by the healthcare provider. For example, transdermal fentanyl will have little analgesic effect for the first 12 hours after initial administration and will reach maximum effect about 18-22 hours after application. There will be a prolonged tapering half life of about 17 hours after steady state is obtained and the patch is removed from the skin. Titration to and from other opioids to transdermal fentanyl must take these issues into consideration when choosing the appropriate dose.

Opioid Rotation
Neurotoxicity can occur with the use, particularly prolonged use, of any opioid. Neurotoxicity symptoms include myoclonus, agitation, delirium, and hyperalgesia. Opioid rotation can be an effective method for addressing inadequate analgesia and unacceptable toxicity profiles. Differing mechanisms of action, efficacies, and propensity for toxic metabolite accumulation, may partially explain the variability of opioids in analgesic response and occurrence of side effects. Similarly, opioid rotation may be necessary when alternative routes of administration are needed, to ensure patient compliance (regimen adherence), or when drug expenses become an issue.

Opioid rotation usually involves abrupt cessation of one opioid and immediate replacement with another at an equianalgesic dose. It is important to note that equianalgesic dosing formulas were not designed for the higher doses used by chronic pain patients. Because of the variability of response between patients, a starting dose of the new opioid should be between 30% and 50% lower than the standard equianalgesic formula, followed by upward titration to satisfactory analgesia.11

Methadone has become one of the most commonly selected opioids to which patients are rotated. The advantages of methadone include low cost, a high degree of bioavailability, and a lack of active metabolites. The disadvantages include its very long half-life, which can lead to accumulation and toxicity in many patients, and its extreme variability of effect in different patients, making selection of an equianalgesic dose particularly challenging. Ultimately, long-term success in controlling cancer pain may require the use of two or three different opioids in rotation.12

Combination Opioid Therapy
As knowledge of the pathophysiology of pain and the molecular and cellular mechanisms of opioid effects evolve, more directed opioid therapy will become available. Multiple opioid receptors – mu, kappa, and delta – play a part in opioid analgesia.13 Furthermore, mu receptors appear to exist in multiple variants. The presence of genetic polymorphism and variances in the distribution of receptors may account for the differences in opioid response.14

Consequently, it has been hypothesized that coadministration of opioids could act synergistically by targeting different receptors, potentially providing improved analgesia with fewer side effects. Preclinical studies have provided some cause for optimism. Ross et al found that subanalgesic doses of morphine and oxycodone coadministered to rats resulted in a substantial analgesic effect.15 Behavioral side effects of the opioid combination were comparable to the saline placebo; doses of either morphine or oxycodone alone, at an equipotent level to the opioid combination, produced sedation.

Combination of an opioid agonist with a low-dose opioid antagonist has also been proposed as a way of minimizing opioid side effects while maintaining analgesia. Several studies have examined the effect of small doses of naloxone in combination with intravenous morphine patient-controlled analgesia (PCA), although none of these studies examined cancer pain. The first of these was a study in which patients undergoing hysterectomies were randomized into three treatment groups: two levels of low-dose naloxone and one saline placebo group.16 The two naloxone groups experienced lower levels of nausea, vomiting, and pruritus compared to the saline group, and the lower of the two naloxone doses allowed for less usage of PCA morphine. A second study in patients undergoing hysterectomies, using only one naloxone group, found no advantage to naloxone administration.17 Two further studies, however, confirmed the benefit of low-dose naloxone. A randomized, double-blind controlled study of 265 patients undergoing surgery of various kinds experienced lower pain levels and lower incidence of nausea and pruritus compared to the morphine only group.18 A recent double- blind randomized controlled study in postoperative children and adolescents comparing intravenous morphine with intravenous morphine plus low-dose naloxone found significantly lower rates of pruritus and nausea in the naloxone group compared to placebo.19 These studies are intriguing, but should not change current practice recommendations at this time.

Pharmacologic Treatment of Breakthrough Pain
Breakthrough pain describes an episodic and transient pain experience above and beyond an effectively controlled baseline pain. Breakthrough pain is the cause of substantial suffering among cancer patients and is associated with significant functional deterioration.20 The occurrence of breakthrough pain among cancer patients has, in recent years, been found to be quite common. Estimates vary, but a range of 60% to 75% of cancer patients experiencing breakthrough pain appears to be a valid estimate.20-22

Typically, breakthrough pain has been treated by parenteral or oral administration of an immediate-release opioid. Oral opioids usually take approximately 20 minutes to reach an initially effective serum concentration and 30 to 50 minutes to achieve peak dose effect. Intravenous or subcutaneous opioids act more quickly, but are infrequently needed for the patient managed in the outpatient setting. Most oral rapid release opioids possess an analgesic effectiveness lasting between three and five hours. Breakthrough pain, though, may often have a rapid onset and short duration. An immediate-release oral opioid, therefore, may reach its required level of efficacy too late to provide necessary analgesia, but will remain in the patient’s system well after the desired additional analgesia is required. In these circumstances, side effects, such as “opioid fog” may linger after the point at which the patient has returned to the baseline pain level.

The introduction of oral transmucosal fentanyl citrate (OTFC) can be effective in treating cancer patients with rapid onset and relatively short lasting breakthrough pain.23 The standard OTFC formulation comes as a solid matrix on a plastic handle, and is administered by sucking on and dissolving the OTFC matrix. Much of the drug is rapidly absorbed by the buccal mucosa and bypasses first-pass metabolism. The onset of pain relief often occurs in about 15 minutes.24 OTFC is indicated for opioid-tolerant patients and should not be used in opioid-naïve patients. Side effects are typical of other opioids.25 Clinical trials have shown that the OTFC formulation provides effective analgesia for most occurrences of breakthrough pain in most patients and continues to be effective for long-term use.26,27

A number of new formulations for breakthrough pain are currently in development. Among these, a nasal morphine formulation is in early trials and has shown promise as an effective analgesic for breakthrough pain. A trial of nasal morphine gluconate in 11 cancer patients found it to be safe and effective in breakthrough pain, with rapid onset of action.28 An intranasal ketamine formulation is also in development. A randomized, double-blind, placebo-controlled trial of 20 patients with chronic pain found intranasal ketamine to be effective for breakthrough pain, with rapid onset and no serious side effects.29

Common Errors in Opioid Use
Numerous errors may occur in the prescribing and administration of opioids. Some of the most common include:

Using as-needed rather than around-the-clock
Administering opioids on an as-needed basis rather than around the clock, particularly in patients experiencing persistent pain, increases the risk of insufficient analgesia and end-of-dose breakthrough pain. The use of long-acting opioids and supplementation with short-acting opioids for breakthrough pain is recommended when ongoing analgesia is required.

Not using rescue medication
Rescue medication for breakthrough or incident pain is necessary to avoid unnecessary pain and suffering. Short-acting opioids or increased doses of the baseline medication have typically been used for breakthrough pain. (See oral transmucosal fentanyl above.)

Not Prophylactically Addressing Side Effects
Side effects ranging from constipation to neurotoxicity are common with opioid use. Most of these can be treated by decreasing the dose with maintenance of efficacy, adding a supplemental agent (as with a laxative for constipation), or by rotating to a different opioid. Unfortunately, side effects frequently go unnoticed and/or untreated causing unnecessary patient discomfort. Some patients would rather experience the pain than the side-effect which can be relatively easily controlled, such as constipation.

Using multiple opioids simultaneously
While the use of combination opioid therapy, as discussed earlier, may lead to more effective treatment of pain with fewer side effects, such treatment approaches are still being studied. Until proven protocols for combination opioid therapy have been established, it is not recommended that clinicians experiment with multiple opioid compound use (except in the case of transmucosal fentanyl for breakthrough pain) as the risks of side effects and toxicity are considerable. Use of two long acting opioids or two short acting opioids concurrently should be avoided.

Conclusion
As cancer research has evolved in recent years, advances in developing agents for the relief of cancer pain have also been substantial. Regulatory and societal barriers to full and effective treatment of cancer pain remain, but are gradually being overcome. At the same time, an expanding array of pharmacologic options are being made available. Within the opioid class, new agents and new routes of administration have recently been introduced to the market, while techniques for their optimal use, such as opioid rotation and combination opioid therapy, are being explored and refined. Patients with a cancer diagnosis should be reassured that in almost all circumstances pain can be adequately managed. An informed patient, a knowledgeable healthcare team, and a commitment to aggressive management of cancer-related or treatment-related pain reflects the highest standard in cancer therapy.

References

1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55(1):10-30.
2. Mott FE, Chakmakjian C, Marcus J. The multidisciplinary management of pain and palliative care in cancer patients: a review. Cancer Therapy. 2004 (2);365-374.
3. Fishbain DA, Rosomoff HL, Rosomoff RS. Drug abuse, dependence, and addiction in chronic pain patients. Clin J Pain. 1992;8(2):77-85.
4. Rupp T, Delaney KA. Inadequate analgesia in emergency medicine. Ann Emerg Med. 2004;43(4):494-503.
5. Mercadante S. Pain treatment and outcomes for patients with advanced cancer who receive follow-up care at home. Cancer. 1999;85(8):1849-1858.
6. Max MB, Payne R, Edwards WT, et al. Principles of analgesic use in the treatment of acute pain and cancer pain. 4th ed. Glenview, IL: American Pain Society; 1999.
7. McNicol E, Strassels S, Goudas L, Lau J, Carr D. Nonsteroidal anti-inflammatory drugs, alone or combined with opioids, for cancer pain: a systematic review. J Clin Oncol. 2004;22(10):1975-92.
8. Mercadante S, Fulfaro F, Casuccio A. A randomised controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: effects on dose-escalation and a pharmacoeconomic analysis. Eur J Cancer. 2002;38(10):1358-1363.
9. Coleman RE. Bisphosphonates: clinical experience. Oncologist. 2004;9 Suppl 4:14-27.
10. Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol. 2000;18(6):1378-1391
11. Bruera E, Kim HN. Cancer pain. JAMA. 2003;290(18):2476-2479.
12. De Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage. 1995;10(5):378-384.
13. Pasternak GW. Multiple opiate receptors: deja vu all over again. Neuropharmacology. 2004;47 Suppl 1:312-323.
14. Lucas LK, Lipman AG. Recent advances in pharmacotherapy for cancer pain management. Cancer Pract. 2002;10 Suppl 1:S14-S20.
15. Ross FB, Wallis SC, Smith MT. Co-administration of sub-antinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats. Pain. 2000;84(2-3):421-428.
16. Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, Perno R. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology. 1997;87(5):1075-1081.
17. Sartain JB, Barry JJ, Richardson CA, Branagan HC. Effect of combining naloxone and morphine for intravenous patient-controlled analgesia. Anesthesiology. 2003;99(1):148-151.
18. Cepeda MS, Alvarez H, Morales O, Carr DB. Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects. Pain. 2004;107(1-2):41-46.
19. Maxwell LG, Kaufmann SC, Bitzer S, et al. The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, r