Analgesic Effects of Nonsteroidal Anti-inflammatory Drugs in Cancer Pain Due to Somatic or Visceral Mechanisms

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1 Vol. 17 No. 5 May 1999 Journal of Pain and Symptom Management 351 Original Article Analgesic Effects of Nonsteroidal Anti-inflammatory Drugs in Cancer Pain Due to Somatic or Visceral Mechanisms Sebastiano Mercadante, MD, Alessandra Casuccio, MD, Antonio Agnello, MD, Salvatore Pumo, MD, Jafar Kargar, MD, and Serena Garofalo, MD Pain Relief and Palliative Care (S.M., A.A., S.P., J.K., S.G.), SAMOT, Palermo, Italy; Department of Anesthesia, Intensive Care and Pain Relief Unit, La Maddalena Clinic (S.M.), Palermo, Italy; Department of Hygiene and Microbiology (A.C.), University of Palermo, Palermo, Italy Abstract The role of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established in the treatment of cancer pain. This class of drugs is considered particularly effective in pain due to somatic mechanisms, although proof of this observation is lacking. To ascertain whether NSAIDs are more effective in specific nociceptive forms of cancer pain, they were administered alone or added to opioids in 32 patients with a sole pain mechanism, somatic pain due to bone metastases (17 patients) or visceral pain (15 patients), respectively. Pain intensity, mean doses of opioids used, and symptoms were recorded after starting NSAID. A significant reduction in pain intensity was found at 3, 7, and 14 days. No differences in pain intensity between the two groups were observed. However, patients with a visceral mechanism required higher opioid doses after a week of treatment. No differences in adverse effects were reported. NSAIDs may be useful drugs in the management of cancer pain, regardless of the mechanism of pain involved. The incidence of adverse effects during prolonged administration should be assessed in future studies. J Pain Symptom Manage 1999;17: U.S. Cancer Pain Relief Committee, Key Words NSAIDs, opioids, cancer pain, adverse effects, pain mechanism, epidemiology Introduction The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is currently suggested by the World Health Organization (WHO) guidelines on cancer pain management. Their role has Address reprint requests to: Sebastiano Mercadante, M.D., Medical Director, Pain Relief and Palliative Care, SAMOT, Via Libertà 191, Palermo, Italy. Accepted for publication: July 30, been well established in the treatment of mild to moderate pain, and when combined with opioids, in the treatment of moderate to severe pain. 1 The analgesic effect of NSAIDs has traditionally been related to the inhibition of peripheral prostaglandin synthesis. This peripheral mechanism, similar to the effect of infiltrating the injured area with local anesthetics, attenuates the sensitization of peripheral nociceptors, afferent nociceptive activity, and, in turn, C-fiber-mediated central sensitization. 2,3 U.S. Cancer Pain Relief Committee, /99/$ see front matter Published by Elsevier, New York, New York PII S (98)

2 352 Mercadante et al. Vol. 17 No. 5 May 1999 A central action of NSAIDs also has been suggested. The presence of a hyperalgesic state seems mandatory for the demonstration of the analgesic effect of NSAIDs in experimental animal studies, 4 probably due to a reduction of the wind-up phenomenon. 5,6 A dissociation between the antinociceptive and anti-inflammatory effects of NSAIDs has been demonstrated. 6,7 Thus, it appears that the traditional difference between central (opioids) and peripheral (nonopioids) analgesics is becoming difficult to distinguish. A synergy between morphine and NSAIDs has been found, both spinally and intravenously. 8,9 This response is possible because the drugs are acting through distinct mechanisms. This may allow significant opioid dose reduction, consistent with the clinical value of this type of combination in the treatment of cancer pain. On clinical grounds NSAIDs have been shown to be effective in some specific cancer pain syndromes, including pain from bone metastasis, soft-tissue infiltration, arthritis, and recent surgery. 10 Anecdotal experience suggests that NSAIDs are more effective against certain types of cancer pain, specifically pain related to injured myofascial tissues, joints, serous membranes, or periosteum. 10 NSAIDs have been claimed to have a major role in the management of bone pain. 11,12 In one study, significantly better pain relief occurred in patients with bone metastases compared to those with tissue or visceral metastases when a NSAID was added to an opioid. 13 Moreover, NSAIDs may also have activity that extends beyond their accepted role as analgesics and anti-inflammatory drugs; for example, these drugs may be involved in the inhibition of bone metastases. 14 However, data to support the conclusion that NSAIDs are more effective in deep somatic pain due to bone metastases do not exist. 14,15 A lack of trials that examine the effectiveness of NSAIDs in bone pain has been stressed. 14 Visceral pain may also be relieved by NSAIDs. 16,17 It has been shown that the analgesic effect of NSAIDs is similar to that produced by opioids in experimental visceral pain. 18 Patients presenting different pain syndromes who received ketorolac because of inadequate analgesia with opioids or opioid-related side effects obtained better pain control after starting the NSAID; with this treatment, opioid doses could be reduced by %. 16,19,20 High doses of NSAIDs have proved to be effective even in neuropathic pain conditions. 21,22 A good analgesic response after a course of NSAIDs has been shown to have a positive predictive value for overall analgesic response in cancer pain patients, regardless of the pain mechanism. 23 To further evaluate the proposition that NSAIDs are more effective in somatic rather than in visceral pain, we planned this study to evaluate NSAID efficacy in cancer pain due to somatic or visceral mechanisms. Methods Four hundred and eleven consecutive patients referred to a home palliative care program were surveyed. All the patients were examined and treated at home and followed until death by a team of doctors and nurses experienced in palliative care. Each patient averaged two to three visits a week. The pain syndromes were considered on the basis of the clinical history, site of pain and known metastases, and other findings, when available. 24 Patients who did not require analgesic therapy, or with multiple causes and mechanisms of pain (e.g., a neuropathic pain mechanism), specific contraindications to the use of NSAIDs, coexisting liver or renal disease, or cognitive impairment, were excluded. Patients with bone fractures and those taking drugs with a potential analgesic effect were also excluded. A prospective study was carried out in a final sample of 32 consecutive advanced cancer patients with pain who had a sole pain mechanism. Of these, 17 patients had a somatic pain mechanism due to bone metastases and 15 patients had visceral pain (stretched, compressed, invaded, or distended visceral structures, with poorly localized pain). NSAIDs alone were administered in patients who had not received any analgesic treatment, or were added to opioids in patients already taking these drugs. Ranitidine or misoprostol was co-administered with the NSAIDs. This approach is part of a protocol commonly used at our institution. The home physicians, each of whom had more than 5 years experience in palliative care, were unaware of the aims of the study and were free to choose the NSAID to use, according to a standard protocol (diclofenac mg daily, naproxen g daily, or

3 Vol. 17 No. 5 May 1999 Analgesic Effects of NSAIDs 353 ketorolac mg daily, by the oral route when possible). Using a standard data collection form, the following parameters were recorded: 1. Pain intensity, assessed by means of a 10 cm visual analogue scale (VAS), before (T0) and 3 (T3), 7 (T7), and 14 days (T14) after NSAID administration began. Pain was evaluated by the patient s self-report, when possible, two to three times a week. 2. Mean dose of opioids, expressed as an equianalgesic dose of oral morphine 1 at T0, T3, T7, and T Patient-rated symptoms and side effect intensity were assessed by means of a scale ranging from 0 to 3 (not at all, slight, a lot, awful) at T0, T3, T7, and T14. Differences between mean doses were analyzed by Mann-Whitney U test and Wilcoxon signed ranks test. Symptom differences were analyzed by the chi-square test, using Yates correction. When the P value was less than or equal to 0.05, a difference was considered to be significant. Results The groups were comparable for gender and age. As expected, different patterns of primary tumors were found, due their typical tendency to give local or distant metastases (Table 1). Diclofenac, naproxen, and ketorolac were used in 18 (10 in S group and eight in V group), five (three in S group and two in V group), and nine patients (four in S group and five in V group), respectively. A statistically relevant difference in pain intensity was observed in each group at T3, T7, Table 1 Characteristics of Patients S patients V patients Age, mean (range) 62 (41 74) 64 (35 76) Sex 9/8 8/7 Primary cancer Lung 5 1 Gastrointestinal 4 Genitourinary 5 4 Breast 7 Pancreas 3 Liver 3 S somatic pain; V visceral pain. and T14 (P 0.001). No differences in pain intensity were found between groups (Table 2). Patients with visceral pain showed an increase in opioid dosage at T7 and T14 (P 0.05) when compared to T3. However, no difference was reported when compared to patients with somatic pain (Table 2). No difference in the number of patients taking opioids was demonstrated in the two groups of patients at the different intervals examined (Table 3). Eight and six patients in groups S and V, respectively, were opioid-naive before starting the NSAID. Of these, four patients in each group remained on NSAIDs at the end of the study. Two patients in group V, who received opioids before starting the NSAID, could stop opioids at the end of the study. The trend of symptom intensity was similar in the two groups (Table 2). No differences were observed in pain intensity, opioid consumption, and symptom rating when using different kinds of NSAIDs, although the number of patients was too low to draw any conclusion. Sweating was reported in three patients, one in the somatic group and two in the visceral group, but it was tolerable and did not require any treatment. Discussion NSAIDs are frequently used in cancer pain, especially in some European countries. In one survey, NSAIDs were the analgesic drugs most frequently used before referral to a palliative care program. 25 In another, NSAIDs were used on 85% of treatment days either alone or in combination with opioids, for an average duration of 66 days. 26 In an Italian survey, the duration of the first step of the analgesic ladder ranged form 19 to 42 days (about half of the referral-death period 25 ), and the duration of this treatment did not exceed 3 weeks in more than 50% of patients, primarily because of limited survival. 27 Long-term administration of NSAIDs, alone or combined with opioids, also was described; these patients complained of somatic and/or visceral pain. The switch to the second step of the WHO analgesic ladder was due to side effects in only 23% of cases, after a mean of 24 days. 27 NSAIDs were used for prolonged periods, or introduced in patients on other steps, to improve analgesia or to avoid increases in opioid dosage, and were suspended

4 354 Mercadante et al. Vol. 17 No. 5 May 1999 Table 2 Pain Intensity, Opioid Dosage in Morphine Equivalent Mg, Gastric Discomfort, Nausea and Vomiting, and Drowsiness in Somatic (S) and Visceral (V) Groups a T0 T3 T7 T14 Pain intensity S b b b V b b b Opioid dosage S V c 28 8 c Gastric discomfort S V Nausea and vomiting S V Drowsiness S V a Data are expressed as mean SE. b P when compared to T0, c P 0.05 when compared to T3. for adverse effects in a minority of cases. About 20% of patients were still taking NSAIDs in the last week of life. 28 The extensive use of NSAIDs has been claimed to explain the use of lower doses of opioids in some countries, like Italy and Germany, that have severe legal restrictions on opioid prescription. Despite these large experiences, there have been very few well-controlled clinical trials of NSAIDs in cancer pain. In this study, patient selection was difficult because most patients had multiple sites, causes and mechanisms of pain 29,30 and we needed to select patients with a sole pain cause to detect some difference on the effects of NSAIDs. NSAIDs were useful both for somatic and visceral pain as the first step of the analgesic ladder, and were also useful in combination with opioids, regardless of the pain mechanism involved. The pain intensity was reduced by NSAIDs administration, while maintaining similar opioid dosages. This effect seemed less durable when visceral pain was the main mechanism of pain, as demonstrated by the necessity to increase the opioid dosage after a week of treatment. In another study, 31 no patient with deep somatic pain achieved satisfactory pain relief with NSAIDs in the first instance and all Table 3 Number of Patients with Somatic (S) and Visceral (V) Mechanisms Taking Opioids at Different Intervals T0 T3 T7 T14 S 8/17 8/17 6/17 5/17 V 6/15 8/15 6/15 6/15 required opioids, as did patients with other pain mechanisms; in contrast, difficult neuropathic pain syndromes, which were not responsive to opioids, were sometimes resolved with high doses of NSAIDs. 21,22 In the present study, all NSAIDs were equally effective and there was no proof that any pain syndrome is more or less responsive to this class of drugs. These data indicate that, like opioids, NSAIDs should not be considered analgesics for a specific type or cause of pain, at least in nociceptive forms of pain. NSAIDs are suggested in the treatment of mild to moderate pain by the WHO guidelines. However, even patients with moderate to severe pain (VAS 4), who reported that pain interfered with activity, mood, and sleep 32 benefited from NSAIDs, even when they were administered alone. This observation is consistent with the results of other studies in patients with cancer pain. 33 A reduction in the daily consumption of opioids using a patient-controlled analgesia system, accompanied by better symptom control, has been reported in short-term studies in cancer patients with different intensities and mechanism of pain. 34,35 Thus, NSAIDs can be more than mild analgesics for a short period of time, although the majority of patients with moderate to severe cancer pain may be expected to require a shift to opioids to achieve satisfactory control of their pain, owing to well-known ceiling effect of NSAIDs. In contrast to the opioids, which can be titrated to achieve pain relief and can be used for prolonged periods of time, the NSAIDs ceiling effect indicates that there is no therapeutic gain in increasing dosages beyond

5 Vol. 17 No. 5 May 1999 Analgesic Effects of NSAIDs 355 those recommended. Higher doses will yield predictable dose-dependent adverse effects, especially in high-risk patients, including the elderly; patients who have preexisting renal or gastrointestinal diseases or hypovolemia or patients who receive other drugs. 36 No relevant adverse effects attributable to NSAIDs were observed. This may be due to the limited period of study, or the use of prophylactic agents, including H 2 inhibitors and misoprostol. The latter drugs are frequently used in association with NSAID treatment, and have been administered in 33% to 46% of patients (almost all the patients who were administered NSAIDs). 28 Renal complications should be expected with prolonged use in patients with risk factors, such as advanced age, preexisting renal disease, dehydration, or concomitant use of drugs. 36 Further research should address this issue in long-term studies. Guidelines in the management of NSAIDs are largely empiric, and are drawn from clinical experience. Individual differences in response to the various NSAIDs are not yet well understood. None of the differences in the adverse effects associated with various nonopioid analgesics have been confirmed in large epidemiologic surveys of patients with cancer pain. 37 Conclusions regarding safe and effective dosages from studies in inflammatory diseases may not directly apply to the treatment of cancer pain in patients who frequently have several serious conditions and commonly receive multiple medications. 37 Although the number of patients was low, no distinction was made among the NSAIDs used in this study. The physicians treating these patients were unaware of the aim of this study and were free to choose their preferred NSAID, as usual, to maintain the unawareness. A similar analgesic effect and a comparatively low morbidity rate of different NSAIDs have been reported in cancer pain. 14,38 Moreover, despite different pharmacokinetic properties, many NSAIDs are effective for longer than their half-lives, probably because they tend to be retained within inflamed tissue. 39 Although it can be useful to identify the most effective drug in cancer patients, sequential trials of different NSAIDs are not feasible and adding opioids should not be delayed. 40 Although it must be recognized that the addition of an NSAID to a therapeutic regimen exposes patients to the side effects of another medication, the use of NSAIDs may be useful in both somatic and visceral pain. This broad analgesic effect may be useful in optimizing the balance between analgesia and side effects, in conditions in which increases in opioid dosage cause opioid toxicity. The presence of side effects and a ceiling effect on their analgesic efficacy suggest that these drugs should only be used for a short time, although they could still maintain their opioid-sparing effect. Caution is needed when using NSAIDs for prolonged periods, as long-term studies with NSAIDs in cancer pain are lacking. Risk factors such as advanced age, preexisting renal or gastrointestinal diseases, hypovolemia, or concomitant use of drugs should be considered. 36 NSAIDs also must be used cautiously in patients predisposed to adverse effects, including the elderly and those patients with prior peptic ulcer disease or impairment of renal function. 37 Caution is also needed if NSAIDs are administered to patients who are receiving medications that enhance toxicity, such as steroids. Variability in the response to individual drugs should be assessed in appropriate multicenter studies including a large number of patients. Finally, effective agents to prevent or limit the adverse effects related to the prolonged use of NSAIDs should be studied. References 1. Hanks GW, Justins DM. Cancer pain: management. Lancet 1992;339: Dahl JB, Brennum J, Arendt-Nielsen L, Jensen TS, Kehlet H. The effect of pre- versus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin. Pain 1993; 53: Dahl JB, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. Br J Anaesth 1991;66: Petersen KL, Brennum J, Dahl JB. Experimental evaluation of the analgesic effect of ibuprofen on primary and secondary hyperalgesia. Pain 1997;70: Malberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 1992; 257: McCormack K, Brune K. Dissociation between the antinociceptive and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs. Drugs 1991;41:

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