Management of cancer pain - Springer Link

Intern Emerg Med (2010) 5 (Suppl 1):S31–S35 DOI 10.1007/s11739-010-0448-8

S Y M P O S I U M : M A N A G I N G O F C O M P L I C AT I O N S I N P A T I E N T S W I T H C A N C E R

Management of cancer pain Sebastiano Mercadante

Ó SIMI 2010

Abstract In the last decades, studies validating the WHO analgesic ladder have been shown to have methodological limitations and different problems are unresolved due to a lack of controlled studies on this subject. These problems include a better definition of the role of NSAIDs, the prolonged use of NSAIDs in cancer pain, and the utility of step 2. Moreover, the indications for using different strong opioids and alternate routes of administration to improve pain relief in difficult pain situations are not well established. The proportion of patients who do not benefit from these treatments remain unclear, and how the opioid response may be improved with the use of adjuvants is also uncertain. This review will offer an update on these problems and the existing therapeutic opportunities. Keywords Cancer pain Opioids Routes of adminsitration WHO method Introduction Pain is a prevalent symptom experienced by at least 30% of patients undergoing an oncological treatment for metastatic disease and by more than 70% of advanced cancer patients [3]. In 1986 the World Health Organization (WHO) published a set of guidelines for cancer pain management based on the three-step analgesic ladder [29]. The main aim of WHO guidelines was to legitimize the prescribing of strong opioids, arising from evidence of poor management of cancer pain, due to reluctance of health care S. Mercadante (&) Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via San Lorenzo 312, 90146 Palermo, Italy e-mail: [email protected]

professionals, institutions, and government to use opioids because of fears of additicon, tolerance and illegal abuse. Its application is reported to achieve satisfactory pain relief in up to 90% of patients with cancer pain. Despite the large experience proving the feasibility and efficacy [15, 27, 30], in the years of evidence-based medicine, the three-step ladder has been criticized for the lack of robust data supporting this approach. In the last decades, studies validating the WHO analgesic ladder have been shown to have methodological limitations including the circumstances during which assessments were made, small sample size, retrospective analyses, high rate of exclusions and dropout, inadequate follow-up, and a lack comparison with levels of analgesia before the introduction of the analgesic ladder [11]. Thus, different problems are unresolved due to a lack of controlled studies on this subject. These problems include, for example, a better definition of the role of NSAIDs, the prolonged use of NSAIDs in cancer pain, and the utility of step 2. Moreover, the indications for using different strong opioids and alternate routes of administration to improve pain relief in difficult pain situations are not well established. The proportion of patients who do not benefit from these treatments remain unclear, and how the opioid response may be improved with the use of adjuvants is also uncertain. Finally, different countries apply the WHO ladder approach differently depending on the availability of drugs.

Steps First step The first step in the WHO analgesic ladder involves the use of a non-opioid with or without an adjuvant analgesic.

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Studies of various non-opioid analgesics, with or without opioids have been assessed. Heterogeneity of study designs and outcomes, and short length of study precluded metaanalyses. From the data available non-opioid analgesics appeared more effective than placebo. No superior safety or efficacy was demonstrated for one of this class of drugs, and slight advantages were found in trials of combinations of an non-opioid analgesic with an opioid, compared with either single entity [13]. Some studies suggest a different place of non-opioid analgesics, administered in patients already on opioids, given first to reinforce analgesia in patients with difficult pain control or who tend to develop adverse effects with increasing doses of opioids [18]. The conclusions of this study are intriguing, because the reluctance of North American physicians to use NSAIDs and conversely the extensive, and sometime exaggerated, use in European countries may find a compromise based on the data pointed out in this work. Patients could be started on opioids alone and then added non-opioid analgesics, for example in conditions where pain is particularly sensible to this class of drugs, or to reduce the tendency to further opioid escalation, when adverse effects tend to develop. Although adverse effects occurred infrequently in previous large experiences, these studies did not specifically assess this issue. The development of ulcer or renal toxicity might not be apparent with short-term dosing [13], and the specific long-term safety profile has never been established in a randomized studies. Second step The role of so-called ‘‘weak opioids’’ in the treatment of moderate cancer pain has been questioned, and it has been speculated that this step could be by-passed. A metaanalysis conducted by Eisenberg et al. [7] reported that no significant differences in pain relief were noted when the use of non-opioids alone was compared to non-opioids plus opioids for moderate pain. However, these results were based on single-dose studies or studies involving a small number of patients, and a regular clinical use would be more effective than would be predicted on data involving single-dose administration. Previous studies underlined the role of opioids for moderate pain (namely codeine, dextropropoxyphene, and codeine), in comparison to morphine in terms of efficacy and adverse effects. In opioid-naı¨ve patients, a more favorable balance between side effects and analgesia occurred when step 2 opioids were administered compared to low doses of morphine used to omit step 2 of the analgesia ladder [9, 14]. On the other hand, other studies assessed the use of strong opioids in opioid-naı¨ve patients, i.e., skipping the second step drugs. Doses of 25 lg/h of fentanyl have been used successfully [24, 25], although it means to administer

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equivalent doses of 60 mg/day of oral morphine, which is a considerable dosage for opioid-naı¨ve patients, having a high risk to produce adverse effects and reduce patient’s complicance. This observation was confirmed in a study where transdermal fentanyl used at doses of 25 lg/h, equivalent to 60 mg of oral morphine, was better tolerated in codeine using patients rather than in opioid-naı¨ve patients [28]. In a more recent study the sequential treatment proposed by WHO was compared with a direct administration of strong opioid as a first step. Treatments appeared equally effective, although the group treated with opioids first had a better pain relief and patients’ satisfaction, and less number of therapeutic interventions. However, nausea was more frequently reported. Only 50% of patients in control group needed strong opioids in doses similar to those used in patients who received strong opioids first [12]. Unfortunately initial doses of strong opioids were not mentioned, making evaluation of data difficult. The choice of the initial doses makes the difference in terms of complicance, efficacy, and tolerability. Doses of morphine, or other strong opioids should be as flexible and as low as those in the range commonly used of opioids for moderate pain. Morphine used at very low doses in opioid-naı¨ve patients may offer different advantages, including a greater tolerability while providing analgesia. The rationale was to replace opioids for moderate pain with morphine used in doses equivalent to the range of doses commonly prescribed at flexible doses in clinical practice [19, 22], and has been confirmed in a subsequent study; 30 mg/day of oral morphine provided excellent analgesia in opioid-naı¨ve patients [6]. Of course, patients with severe pain are already candidates to receive strong opioids at consistent dose of about 60 mg/day of oral morphine equivalents, according to the WHO guidelines, so that this approach should be reserved for patients with moderate pain, potentially requiring step drugs. Third step Morphine is the most frequently used opioid in cancer pain management. Although morphine remains a cornerstone for the management of cancer pain, due to the large experience existing among physicians and wide availability in a variety of formulations, no clear data exist about the superiority of one opioid over another [10, 21, 22]. A substantial minority of patients treated with oral morphine (10–30%) do not have a successful outcome because of excessive adverse effects, inadequate analgesia, or a combination of both adverse effects and inadequate analgesia [5]. Individualization of therapy has been emphasized to minimize the side effects and to improve the opioid response. It is now recognized that individual


patients vary greatly in their response to different opioids. Patients who obtain poor analgesic efficacy or tolerability with one opioid will frequently tolerate another opioid. A shift from one opioid to another is recommended when the adverse effect/analgesic equation is skewed towards the side effect component, despite an aggressive adjuvant treatment. Opioid rotation has been shown to be useful in opening the therapeutic window and in establishing a more advantageous analgesia/toxicity relationship. By substituting opioids and using lower doses than expected (according to equivalency conversion tables), it is possible in most cases to not only reduce or relieve the symptoms of opioid toxicity and to manage patients who are highly tolerant to previously used opioids, but also to improve analgesia and thus the opioid responsiveness. This strategy uses much lower doses of alternative opioids in patients who are unresponsive to high doses of morphine [20]. The biological basis for the individual variability in sensitivity to opioids is multifactorial and some aspects remain unclear [16]. Although the conversion ratio between opioids in such circumstances remains unpredictable, morphine, oxycodone, and hydromorphone seem to be more manageable in the clinical context. Differently from other opioids, methadone, which is chemically distinct from morphine, oxycodone, or hydromorphone, shows some particularities which make this drug unique. Individual response varies remarkably from opioid to opioid, due to asymmetric tolerance, different efficacies, pharmacokinetic profiles, and extra-opioid effects, like an anti-NMDA effect, although the clinical ‘‘weight’’ remains to be established in cancer patients. The correct conversion ratio from morphine to methadone is quite complex and particularly debated in literature. It seems that the previous dose of morphine is determinant in the choice of the following dose of methadone in a proportional way. However, there are many factors which may infer the conversion ratio [1, 23]. The concepts of equianalgesia are hard to apply in the clinical setting where patients suffer adverse effects from opioids with poor analgesia in most circumstances, a critical condition which requires immediate intervention. Patients highly tolerant and who are receiving high doses of opioids unsuccessfully should be carefully monitored.

Alternative routes Many patients will develop tolerance to most of the undesirable side effects of opioids (such as nausea/vomiting or sedation) over a period of several days. However, certain patients may not be able to tolerate oral medications because of oesophageal motility problems or gastrointestinal obstruction (e.g., head and neck or oesophageal cancer, bowel obstruction) or may present nausea and vomiting,

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limiting the utility of the oral route. Finally, some patients are unable to swallow due to the site of their cancer or because they are neurologically impaired. In these cases, an alternative form of analgesia must be used. Alternative route, including the intravenous and subcutaneous, as well as the transdermal ones, have been advocated in such circumstances [4]. The intravenous route of administration is indicated for those patients whose pain cannot be controlled by a less invasive route or already having a central venous access. The major disadvantage of this route is that it is more complex to manage, especially at home, and requires some expertise. On the other hand, this route is the faster one, allowing for an immediate effect in emergency conditions. Different opiods are available as an intravenous solution in the majority of countries, including morphine, hydromorphone, fentanyl, alfentanil, sufentanil, and methadone. For patients requiring parenteral opioids who do not have indwelling intravenous access, the subcutaneous route can be used. This simple method of parenteral administration involves inserting a small plastic cannula on an area of the chest, abdomen, upper arms, or thighs and attaching the tubing to an infusion pump. The limiting factor is the volume of fluid that can be injected per hour, often requiring more concentrated solutions. Most drugs used by intravenous route can also be used by subcutaneous infusion, unless methadone, which could induce local toxicity. The oral–parenteral ratio for morphine is 2:1 or 3:1 [10]. Intravenous or subcutaneous opioid infusions can be given as continuous infusions or by a PCA device which provides continuous infusion plus on-demand boluses. Confused or not collaborating patients may not be the best candidates for PCA use. The transdermal route is a very comfortable route of administration. For patients who are unable to take oral medications, the transdermal route is a priority option for maintaining continuous plasma concentrations of opioids. Two drugs are available, fentanyl and buprenorphine, due to their potency and lipophilicity. It has been suggested to use a conversion transdermal fentanyl–oral morphine ratio of 1:70–100. For buprenorphine, the buprenorphine–oral morphine conversion ratio ranges from 1:60 to 1:80. The sublingual administration of opioids is particularly beneficial in the patient with cancer who is unable to tolerate oral administration because of nausea/vomiting or dysphagia. It may also be attractive in patients who cannot receive parenteral opioids because of the lack of venous access or presenting typical contraindications for subcutaneous drug administration. Because sublingual venous drainage is systemic rather than portal, hepatic first-pass elimination can be avoided. On the other hand, the transmucosal or sublingual route also offers the potential for more rapid absorption and onset of action relative to the

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oral route. This is particularly useful for treating breakthrough pain, which requires a fast opioid effect. Lipophilic drugs are better absorbed than hydrophilic drugs. For these reasons fentanyl and buprenorphine are prevalently used by this route. Transmucosal fentanyl is the only medication that has been found to be a very useful tool in the management of breakthrough pain in cancer patients in different controlled studies [8].

buccal mucosa and enters the blood stream. The remaining amount is swallowed and about one-third of this part is absorbed, thus achieving a total bioavailability of 50%. However, this approach requires an active participation and collaboration of patients, who are not often able to use the stick. New formulations, such as effervescent preparation, intranasal or sublingual fentanyl, provide rapid analgesia and seem to be more acceptable for patients [8].

Treatment of breakthrough pain

Adjuvants

Breakthrough pain has been defined as a transitory increase in pain intensity on a baseline pain of moderate intensity in patients on analgesic treatment regularly administered. However, transitory pain may occur in patients with no baseline pain at all. Moreover, pain exacerbations may also occur in patients with a severe baseline pain in uncontrolled situations. The intermittent pain may be induced by movement, defined as incident pain, or may be not related to activity and less predictable [26]. A rescue dose of opioid can provide a means to treat breakthrough pain in patients already stabilized on a baseline opioid regimen. The use of a short half-life opioid, such as immediate release morphine, is suggested. The size of the most effective dose remains unknown, although clinicians suggest a dose roughly equivalent to about 15% of the total daily opioid dose administered as needed every 2–3 h. Titration of the rescue dose according to the characteristics of breakthrough pain should be attempted in an individual way to identify the most appropriate dose, as the approach to opioid supplemental dosing has been based solely on anecdotal experience. However, the onset of action of an oral dose may be very slow (more than 30 min) and better results may be obtained with a parenteral rescue dose. Although the intravenous route is the fastest, subcutaneous administration is associated with an acceptable onset of effect and should be considered equivalent in terms of efficacy. PCA is an interesting modality to deliver drugs as needed. It appears that the demand dose is more important to the success of PCA and the initial set-up of the patient-controlled analgesia system will influence the therapeutic outcome. However, there are limitations in the use of such pumps. Oral transmucosal dosing is a recent non-invasive approach to the rapid onset of analgesia. Highly lipophilic agents may pass rapidly through the oral mucosa avoiding the first-pass metabolism achieving active plasma concentrations within minutes. Fentanyl, incorporated in a hard matrix on a handle, is rapidly absorbed. It has been shown to have an onset of pain relief similar to intravenous morphine, that is within 10–15 min. When the fentanyl matrix dissolves, approximately 25% of the total fentanyl concentration crosses the

Adjuvants comprehend a wide range of drugs, commonly prescribed to improve opioid analgesia. Antidepressants and antiepileptics are most frequently administered as co-analgesics in the presence of neuropathic pain, in combination with opioids. Despite the relative efficacy demonstrated by this class of drugs in chronic non-cancer conditions, evidence of the benefit of such combination in cancer pain management is weak. Gabapentin proved to be effective in reducing the mean global score and dysesthesia, but not allodynia, compared to placebo in people with neuropathic cancer pain that was not adequately controlled by systemic opioids [2]. However, the magnitude and duration of benefit for patients remain questionable in clinical practice. Similarly, amitriptyline added to opioids was able to reduce the worst pain only, while producing more central adverse effects, in comparison to patients receiving opioids alone [17]. Thus, the role of adjuvants remains poorly defined, at least in advanced cancer patients receiving opioids, and require further data in well-designed and robust studies. In particular, the timing of starting these drugs, which potentially should be started at the first step with nonopioid analgesics, considered to be poorly effective for neuropathic pain, are given first.

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Conclusion WHO method remains of paramount importance and should continued to be encouraged when approaching advanced cancer patients with pain, for the high chances of success, ranging between 70 and 90%. Despite the lack of strong evidence to produce unbiased estimates of the proportion of patients in whom the ladder produces satisfactory results and the fact that no controlled studies with other methods have been conducted to assess its validity, there is the risk to underestimate the educational meaning of this simple approach. Although these guidelines can be implemented, currently the correct use of the WHO method can lead to adequate long-term pain control in most patients with advanced cancer disease. Wider dissemination of the WHO


guidelines among healthcare workers is still necessary to raise the standard of treatment before introducing further non-validated treatments, as many cancer patients still suffer from unrelieved pain due to inappropriate pain management, insufficient knowledge and education, the physician’s limited experience regarding the management of cancer pain, and the perception of the laws that govern opioid prescription and use. It seems clear, however, that individualization of the treatment still remains the key of the best treatment. For these reasons a profound knowledge of drug characteristics and a good experience in evaluating the patients’ response, also recognizing the possible alternative treatments, still remain the key of success. Conflict of interest

None.

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