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Opioid titration in cancer pain: A critical review
European Journal of Pain 11 (2007) 823–830 www.EuropeanJournalPain.com
Review
Opioid titration in cancer pain: A critical review Sebastiano Mercadante
*
Anesthesia and Intensive Care Unit & Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Palermo, Italy Palliative Medicine, Department of Anesthesia, Intensive Care and Emergencies, University of Palermo, Italy Received 4 November 2006; received in revised form 22 December 2006; accepted 15 January 2007 Available online 28 February 2007
Abstract Initiation of therapy with strong opioids is a challenging phase to obtain the maximum benefit and to gain the patient’s compliance. The approach could be different, depending on the clinical situation and type of opioid regimen. Substantially, the need to titrate the dose of strong opioids emerges in different conditions: (a) in opioid-naive patients who require an opioid treatment; (b) in patients no longer responsive to weaker drugs requiring strong opioids; (c) in patients already receiving strong opioids requiring higher doses because of an increase in pain intensity or a new acute pain problem; (d) in patients who are severely suffering and need an intensive as well as rapid intervention, due to previous persistent undertreatment. Whilst there is a vast literature confirming the effectiveness of most opioid drugs for the treatment of chronic pain, there is a lack of information regarding opioid titration. This review assesses the principal titration methods and outcomes regarding the different opioid drugs and their modalities of administration, in different clinical contexts. Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Cancer pain; Opioid titration
1. Introduction Most cancer pain responds to pharmacological measures, and successful treatment is based on the administration of analgesics, according to the WHO analgesic ladder. Strong opioids should be used if pain is unrelieved by weak opioids or is severe at the outset. The regular use of morphine by mouth has done much to improve the management of pain in advanced cancer. Oral morphine is conventionally the opioid of choice, because of its established effectiveness, availability, familiarity to physicians, simplicity of administration, and relative cost. However, information regarding alternative opioids is improving. Some of these drugs may be useful for their specific physical and pharmacological *
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characteristics and are currently used with outcomes similar to those observed with the use of morphine (Hanks et al., 2001). From a clinical point of view, the use of different opioids with specific characteristics and modalities of administration, may require different approaches to face a particular clinical situation. Initiation of opioid therapy is a delicate and challenging phase to obtain the maximum benefit and to gain the patient’s compliance. This means that a careful balance between a rapid pain control and the possible development of adverse effects is imperative. There are different clinical scenarios which may require different approaches. One is represented by opioid-naive patients who require an opioid treatment. Another clinical situation is represented by patients who are no longer responsive to weaker drugs and require strong opioids. Moreover, patients already receiving strong opioids may require higher doses during the course of disease,
1090-3801/$32 Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2007.01.003
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due to an increase in pain intensity or a new acute pain problem. Finally, some patients who are severely suffering, often due to undertreatment, may need a more intensive and rapid intervention. The latter condition will require higher levels of expertise and more complex approaches. The aim of this article was to critically review the principal titration methods and outcomes described in literature regarding the different opioid drugs and their modalities of administration, also taking into account the different clinical contexts. Comments included in this review should be considered as personal opinions and are open to further criticism and discussion. 1.1. Search strategy and selection criteria Data for this review were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using the search term ‘‘opioid titration’’. Abstracts and reports from meetings were also included. Only articles published in English between 1980 and 2005 were included. Additional hand searching was performed from pain and palliative care journals, as well as personal files. From the reference lists, key textbooks and previous reviews were searched for additional studies. Considering the predictable poor homogeneity of patients, the different purposes and clinical settings, no attempt to perform a meta-analysis was done. Papers were also re-ordered according to the different clinical contexts to have a more didactic overview, and then were critically reviewed. 1.2. Opioid titration in opioid-naive patients Opioid-naive patients receiving non-opioid analgesic drugs unsuccessfully may have moderate-severe pain. According to WHO guidelines patients should be started with opioids for moderate pain, including codeine, tramadol, or dextropropoxyphene. The role of ‘‘so called weak opioids’’ in the treatment of moderate cancer pain has been questioned, and it has been speculated that the second step of analgesic ladder could be omitted (Eisenberg et al., 1994). Opioids for moderate pain have been compared with morphine. In opioid-naive-patients, a more favorable balance between side effects and analgesia occurred when step two opioids were compared to low doses of morphine (Mercadante et al., 1998a,b; Grond et al., 1999). However, comparison was based on doses of morphine which could be considered relatively high in opioidnaive patients, who are at higher risk of developing adverse effects. Recent studies have assessed the use of strong opioids in opioid naive patients skipping the second step drugs. Starting doses of 0.6 mg/day of fentanyl have been used
successfully (Mystakidou et al., 2001; Mystakidou et al., 2002; Mystakidou et al., 2003; Mystakidou, 2004). According to this information it should be assumed that doses of 0.6 mg/day of fentanyl TTS can be safety used in opioid-naive patients. Despite such optimistic outcomes, these findings are unrealistic. This is unlikely to occur in the raw clinical setting, due to the high risk of producing adverse effects and reducing patient’s compliance. This observation was confirmed in a study where fentanyl TTS used at doses of 0.6 mg/day, was better tolerated by patients receiving codeine rather than in opioid-naive patients, who stopped the treatment prematurely in 21% of cases (Vielvoye-Kerkmeer et al., 2000). In another study comparing oral morphine and fentanyl TTS, a high percentage of patients among opioid-naive patients starting strong opioids (fentanyl TTS 0.6 mg/day or oral morphine 60 mg/day), developed moderate-to-severe adverse effects. Of interest, only about half patients completed the four week period of observation (van Seventer et al., 2003). Similarly, opioid-naive patients receiving 0.6 mg/day of fentanyl TTS developed relevant adverse effects in comparison with patients previously treated with opioids, and were more likely to withdraw because of adverse effects (Tawkfik et al., 2004). The sequential treatment proposed by WHO has been compared with strong opioids used as the first step. Treatments appeared equally effective, although the group treated with opioids first had a better pain relief and patients’ satisfaction, and a minor number of therapeutic interventions. However, nausea was more frequently reported. Only 50% of patients in the control group needed strong opioids in doses similar to those used in patients who received strong opioids first (Marinangeli et al., 2004). Unfortunately, the initial doses of strong opioids were not mentioned, making evaluation of data difficult, although among the drugs is reported fentanyl, of which the minimal existing dose in Italy is 0.6 mg/day. A similar approach has been recently proposed, showing that strong opioids may provide advantages over the traditional strategy in terms of the percentage of days with worst pain, but also require careful management of side effects (Maltoni et al., 2005). Interestingly, patients who started morphine 60 mg/day, a dose which is more or less equivalent to fentanyl 0.6 mg/day, after receiving weak opioids, developed adverse effects and titration was delayed in about 25% of patients. This occurred despite patients were not opioid-naive (Klepstad et al., 2000a,b). It is likely that opioid-naive patients are more susceptible to adverse effects related to relatively high opioid doses. Morphine used at very low doses in opioid-naive patients may offer different advantages, including a greater tolerability during dose titration while providing
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effective analgesia. The rationale was to replace opioids commonly used for moderate pain with morphine used in doses equivalent to the range of activity of second step drugs, commonly prescribed in clinical practice. In a recent trial, titration started with doses of 10– 15 mg/day of morphine, was well tolerated even by older patients, who could be effectively titrated reporting similar effects to those found in adults. Mean doses of less than 45 mg/day of morphine were achieved four weeks after, which means that initiating with 60 mg/day would translate in overdosing (Mercadante et al., 2006a,b). Similar data were reported with minimal doses of oxycodone (Koizumi et al., 2004). Some authors suggested to use an occlusive dressing between the fentanyl patch and the skin to reduce the rate of absorption, providing a dose of 0.3 mg/day and doubling the duration of effect (Peng and Sun, 2005). This method seems to be intuitively unreliable. No scientific data is available in literature with a patch of 12.5 mcg/h. According to this data, opioids for moderate pain may still have a role in the second step of the analgesic ladder. The role of strong opioids is less defined. It is likely that the doses of 60 mg oral morphine equivalents in opioid-naive patients, may produce strong analgesia but are likely to induce more consistent adverse effects. Thus, such doses should be reserved to patients who have received opioids for moderate pain unsuccessfully (see below). Alternately, if the intention is to avoid step 2, morphine or oxycodone titration should be started at the lowest level, as many patients may have a good response with low initial doses of morphine. Doses of 25 mcg/h of transdermal fentanyl (0.6 mg/day), corresponding to a large range of oral morphine (about 60 mg/day), should not be recommended for opioidnaive-patients. In some countries a 12 mcg/h patch is now available, but no scientific data about the use of this dosage has been reported yet. 1.3. Opioid titration in patients who have received weak opioids unsuccessfully 1.3.1. Oral opioids The use of morphine in patients switched from weak opioids has no major influence on aspects of healthrelated quality of life, other than pain (Hwang et al., 2003; Klepstad et al., 2000a,b; Mercadante et al., 2006a,b). The simplest method of dose titration has been provided by EAPC recommendations. During dose titration it is preferable to use an immediate release formulation of morphine that has a rapid onset and a predictable effect. A dose of immediate-release oral morphine is given every 4 h and the same dose for breakthrough pain given as often as required. Patients changing from a weak opioid will usually start with 10 mg every 4 h (60 mg/day). A rescue dose of 16% of
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the total daily dose of the used opioid is commonly prescribed. The total daily dose of morphine should be reviewed daily, based on the assumption that steady state of morphine is reached in about 24 h. If pain returns before giving the regular dose, the regular dose should be increased (Hanks et al., 2001). This approach is suggested by pharmacological observations: peak plasma concentration usually occurs within the first hour after administration of an immediate release formulation of morphine, while controlled release morphine tablets produce delayed peak plasma concentration, after 2–4 h. Recent studies tried to support this approach. A morphine titration schedule has been used in a prospective case series involving 40 patients. Patients receiving rescue ketobemidone were started with immediate release oral morphine 60 mg daily and the dose was increased 33–50% each day (60 mg, 90 mg, 120 mg, 180 mg/day) to obtain satisfactory pain relief. The mean daily morphine dose after titration was 97 mg and the time needed for stopping titration was 2.3 days. Dose titration was postponed in nine patients due to sedation. Constipation and nausea significantly increased after starting morphine. More than 80% of patients were satisfied with the pain treatment (Klepstad et al., 2000a,b). However, at these low levels of pain intensity any judgement is disputable: pre-titration level pain intensity using ketobemidone as a rescue drug was not relevant, and pain intensity passed from a mean pre-titration value of 32 mm (which could be considered by most clinicians as a tolerable level of pain intensity) to 16 mm on a visual analogue scale, at the end of titration. Despite the large use of opioids in cancer pain management, however, these recommendations are flawed by the lack of objective data. The delay in achieving peak plasma concentrations, the attenuation of peak plasma concentrations, and the long duration of action potentially make the use of sustained-release preparations for initial dose titration more difficult. This EAPC statement was contradicted by a recent controlled-randomized, double-blind, double-dummy study comparing titration with immediate-release morphine given 4hourly with titration with sustained-release morphine given once daily. Morphine dose titration was concluded within 2.1 and 1.7 days, respectively (Klepstad et al., 2003). This means that the preliminary use of immediate-release morphine is not strictly necessary. However, these data should be interpreted with caution, as pretitration pain intensity was really mild, as in the previous study (Klepstad et al., 2000a,b), suggesting a floor effect. Thus, no conclusion about the preference of immediate or sustained release can be drawn. It is important to guarantee patients with an adequate dose of immediate release formulation as needed during the dose titration, independently from the use of regular
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immediate or sustained release formulation used as a basal opioid regimen. 1.3.2. Transdermal opioids The use of trandermal (TTS) drugs has been increasing in the last decade, particularly fentanyl TTS. The initial dose finding with fentanyl TTS is often unsatisfactory in patients with unstable pain, as some patients may require early and frequent dose increments to achieve pain control, and steady-state plasma concentrations are delayed in comparison with oral opioids, due to the peculiarity of this delivery system. According to these observations, fentanyl TTS should not be indicated for opioid titration and should be recommended after pain is controlled by other opioids (Hanks et al., 2001). Nevertheless, there are several studies reporting the use of fentanyl TTS in these circumstances. A simple and logical approach could be that patients are provided with rescue medication and encouraged to take this, especially in the first 48–72 h after patch application. Doses can be re-calculated before the next application (Donner et al., 1996). In ambulatory patients who failed an adequate trial of opioids used for moderate pain, fentanyl TTS started at doses of 0.6 mg/day was safe, also providing a reduction in pain score over the 7day study period, and a progressive decrease in rescue medications (Hammack et al., 1996). Alternative approaches have been suggested, including day-to-day titration to initiate fentanyl TTS. The minimal dose was 0.6 mg/day, which was started in a miscellanea of patients, including opioid-naive patients, patients receiving weak opioids, or strong opioids in the range of 0–88 mg of oral morphine equivalents. Titration was repeated every day with an additional patch, until adequate pain control was achieved, unless adverse effects occurred. Morphine was used as a rescue medication. Satisfactory analgesia was achieved within 24–48 h. About half of patients needed dose increases, opioidnaive patients requiring fewer dose increments than opioid-treated patients (Korte et al., 1996). Despite the favorable outcome reported by authors, adverse effects were of concern, for different reasons, in three patients. In vulnerable outpatients, who do not have intensive monitoring, this procedure could be risky, as analgesic serum concentration may not be achieved in some patients before 24 h, due to the large interindividual variability (Portenoy et al., 1993). 1.3.3. Parenteral opioids Opioids, given parenterally, may produce fast and effective plasma concentrations in comparison with oral or transdermal opioids. This means that dose stabilization can be achieved in a shorter period of time. In a comparative study oral morphine was titrated, according to EAPC recommendations, with 5–10 mg
every 4 h, and the same dose was provided as needed, while the intravenous group received boluses of 1.5 mg every 10 min. Subsequently, after finding the effective dose by titration, the total daily dose was converted to oral morphine (Harris et al., 2003). As expected, satisfactory pain relief at 1 h was achieved by most patients in the intravenous group, in comparison with the oral group, while no differences in pain intensity and adverse effects were found 24 h after. The time course reflects the characteristics of the routes, intravenous being faster because of the short lag-time between injection and effect (initial 3 min, peak 30 min) in comparison with oral dosing (initial 15–30 min, peak 45– 60 min). This kind of advantage is evident in the first hours after administration, when more intravenous boluses were allowed, rather than 24 h after, when repeated dosing of oral morphine in both arms provide similar effects. The main potential of patient-controlled analgesia (PCA) lies in the individual titration of the analgesic dosage by providing rapid pain relief for a wide range of requirements. Patients with severe cancer pain and insufficient analgesia with step 2 analgesic drugs were titrated with morphine delivered intravenously by a PCA pump set with a bolus dose of 1 mg, lock-out time of 5 min, and hourly maximum dose of 12 mg (Radbruch et al., 1999). Significant pain relief was achieved within 24 h with mean doses of 32 mg/day of intravenous morphine, which were then converted to a mean of 139 mg equivalent of oral morphine (including PCA doses). In a minority of patients who were assessed with this aim, the mean time to achieve sufficient analgesia was 6 h. Adverse effect intensity was mild, mostly present before starting the study. In conclusion dose titration with oral opioids, particularly with short-onset drugs such as morphine, may provide adequate pain relief in about 48 h in most patients. Although the majority of studies regarded morphine, oxycodone and hydromorphone, which have a similar pharmacokinetic profile, are expected to produce a similar outcome. According to available data, one could also argue that most opioids, even long-acting preparations, can be safety and effectively used, if doses as needed are provided to make appropriate dose adjustments until stabilization is achieved. Similarly, transdermal drugs may also be effective, if combined with adequate measures, able to cover the first 24 h, with short-onset opioids administered as needed. Long-acting opioids, both orally or transdermally, should be started at low doses and effects should be carefully monitored before any change in dose. Parenteral opioids may accelerate the timing for achievement of adequate pain relief. The daily dose could subsequently be converted to the oral route. The common parenteral-oral ratio for morphine is 1:2.5 (Hanks et al., 2001).
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1.4. Patients who are receiving strong opioids and require dose adjustment 1.4.1. Oral and transdermal opioids With inadequate pain relief, opioid doses have to be increased stepwise, that is with a dose increase of 33– 50% every 24 h (Hanks et al., 2001). If pain is responsive to the opioid used, further dose increments often result in enhanced analgesia. This approach can require several days or even weeks until adequate pain relief is obtained. Several studies have assessed the opioid response in time using an escalation index, which provides a simple tool to record the need of opioid escalation in time (Mercadante et al., 1999). For example the opioid escalation index of methadone is lower when compared with that of morphine (Mercadante et al., 1998a,b). The occurrence of adverse effects may limit the dose escalation. This process is based on an individual response which depends on several factors (Portenoy et al., 1990). The opioid response may change in time, due to the intervention of numerous factors. This issue is beyond the aim of the present article. 1.4.2. Parenteral opioids Data on the use of parenteral opioids in patients requiring increasing doses of oral or transdermal opioids is lacking. In one study, the efficacy of the start of parenteral opioids was prospectively assessed in patients who failed with oral or transdermal opioids. A subcutaneous infusion of different opioids was started on 50– 70% of the equianalgesic dose, a median of 80 mg/day of intravenous morphine equivalents, and rescue doses were offered as needed (Enting et al., 2002). Doses were titrated up to 135 mg of intravenous morphine equivalents obtaining a good pain control in more than 50% patients within 48 h. Of interest, no significant changes in adverse effects was evidenced. The variability in the second evaluation time (1–27 days), when an important improvement was seen in 71% of patients, make data on follow-up difficult to evaluate. 1.5. Emergency treatments for patients with severe pain Differently from most cancer population, which may have moderate pain intensities and require simple and soft titration schedules, cancer pain may present as an emergency. Emergency is commonly defined in accordance with severity (pain intensity of 8/10 or greater on a numeric rating scale), duration, and progression over time. Acute severe pain requires rapid application of powerful analgesic strategies and aggressive treatment, which are distinct from chronic management techniques. Patients who present with a pain emergency may receive a regular treatment which has been rapidly loosing efficacy or may have important changes of pain causes. Alternately, patients may present excruciating
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pain of weeks or months duration, largely undertreated. Often they do not receive any opioid. As their optimal dose is unpredictable, a traditional titration could take several days and will result in unuseful suffering for patients. In these circumstances, it could be advisable to expedite opioid titration using the fastest methods. Intravenous titration has been found to be more rapid than oral titration (Harris et al., 2003). In a randomized clinical trial subcutaneous morphine titration required more time and higher doses than intravenous titration in patients with exacerbation of cancer pain (Elsner et al., 2005). Boluses of intravenous and subcutaneous morphine were given every 5 0 and 30 0 , respectively. Doses were proportional to the previous daily opioid consumption and were 2 mg and 10 mg, respectively, for patients receiving less or more than 120 mg of oral morphine equivalents. It is likely that authors assumed that after 30 min doses of intravenous morphine allowed in five boluses of 2 mg would be equivalent to the dose administered by subcutaneous route (10 mg) reaching a peak at the same time of that presumed for subcutaneous route. Titration stopped after patients achieved similar pain intensity in the two groups, within a mean of 53 and 77 min, respectively, and percentage of patients with 30% and 50% pain relief was higher in the intravenous group, despite having initial higher scores of pain intensity. A factor of 1:6.6 for the intravenous titration dose to the daily requirement of oral opioids was found four days after titration. However, this factor was only 3.7 in the subcutaneous group. As data for calculation was made for a limited number of patients, no conclusion can be drawn. As expected, 24 h after and later the results regarding pain relief and adverse effects were comparable. Of interest, as reported in other studies, some symptoms, such nausea, may improve rather than worsen after pain control is achieved. From a pharmacokinetic point of view, total availability and rapid effective plasma concentrations, required for a timely intervention are best achieved with the intravenous route. Titration with intravenous morphine may provide fast and efficient pain relief, also providing information about the amount of opioid necessary for a subsequent treatment. The use of intravenous morphine for these purposes is not new, as more than twenty years ago titration with very high doses of intravenous morphine had already been reported to be effective and safe even in outpatients (Adams et al., 1984; Citron et al., 1984) and more recently in particular settings, at home and in children (Elsner et al., 2000; Mollet and Piquard-Leandri, 1999). However, physicians have been reluctant in using intensive procedures because of the possible risks and poor familiarity with the intravenous route. In recent years a growing interest in palliative care and skills in other routes of administration prompted physicians to face more aggressive
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measures to improve the efficacy of analgesic interventions in some difficult conditions. Different approaches, while similar, are different as intensity, rapidity and safety issues are supported by different rationale and pharmacokinetic strategies. In a pilot study of patients receiving high doses of oral morphine equivalents (median 1530 mg) unsuccessfully, 10–20 mg of intravenous morphine were administered over 15 min and the dose doubled every half hour until pain was controlled (5 or less on a numeric rating scale from 0 to 10). Satisfactory relief of excruciating pain was achieved within a mean of 90 min. Maintenance analgesia was then instituted according to the amount of boluses administered (Hagen et al., 1997). In a retrospective analysis of a large number of patients reporting a pain intensity of at least 5/10, repeated boluses of 1.5 mg of morphine, intravenously every 10 min, were given to an end-point of either total pain relief or drowsiness. This approach provided total pain relief in 79% of patients, with a dose range of 1.5–15 mg of morphine for most patients. About 1/3 of patients reported consistent adverse effects, 32% of patients were drowsy at the end of the procedure, and in 10% this was the indication to stop titration. However, adverse effects were never troublesome (Kumar et al., 2000). This approach was proportional to the entity of the problem, as patients with a not severe pain intensity were also included. Familiarity with opioid pharmacokinetics and pharmacodynamics and clinical experience are helpful in selecting the most appropriate analgesic strategy. Morphine administered as an intravenous bolus exerts an effect within few minutes. The time of peak blood level and the time to peak analgesia have a hysteresis, corresponding to the delay in passing the blood–brain barrier, due to the low lipid solubility of morphine. Thus, the end-point should not be complete pain relief, but the trend observed after some minutes, as it is expected that the major effect will be apparent with a certain delay. On the other hand, repeated small boluses, while less effective, can be confounding, as multiple pharmacokinetic curves may overlap. For example, from the series above described, the maximum bolus of morphine was 34.5 mg. This means that these patients received 23 boluses of 1.5 mg every 10 min in 215 min. In the meantime most of the initial amount of morphine boluses are largely eliminated, so that the real effective dose is difficult to determine. This can explain the intravenous-oral ratio of 1:1 used by authors for oral conversion. A method of rapid titration with intravenous morphine for severe cancer pain and immediate oral conversion was explored using a more intensive approach (Mercadante et al., 2002). Intravenous boluses of 2 mg every 2 min were given to patients presenting severe pain, graded 7/10 or more on a numeric pain scale 0– 10. The target to stop titration was not the pain relief,
rather patient’s detection of significant analgesia or the occurrence of severe adverse effects, regardless of the previous analgesic treatment. The total dose administered was assumed to last approximately 4 h and was then computed for 24 h. The intravenous daily dose was converted to oral morphine using a ratio of 1:3. In patients requiring high doses of intravenous morphine or frail patients, a more prudent ratio was used (1:2, that is 120 mg/day in the previous example). Oral dosing was recalculated on a daily basis, according to the global opioid consumption. A significant decrease in pain intensity was achieved in a mean of 9.7 min with a mean dose of 8.5 mg of intravenous morphine. Patients were discharged within a mean of 4.6 days, with a mean dose of oral morphine of 131 mg/daily and acceptable pain control. Thus, the total amount of morphine required during intravenous titration may be the basis to determine an adequate dose of an oral sustained release formulation to facilitate discharge at home. No immediate significant adverse effects were reported after titration with intravenous morphine. It is important to consider the lag-time between the initial effect (within minutes) and peak effects (about half-hour) of intravenous morphine, due to a delay of morphine in passing the brain barrier. Therefore, the target of the decisionmaking process is the trend of pain intensity between the bolus intervals, rather than a complete pain relief. Careful observation and judicious bedside clinical assessment are the best guides for further intervention. This does not result in an increased risk. Apart from the intensive care setting, where the study was performed, assuring resuscitation expertise, experimental studies have suggested that the presence of pain makes the occurrence of respiratory depression unlikely (Borgbjerg et al., 1996). It is interesting to note that in this latter study no patient required a decrease in the oral morphine dose after conversion, confirming that patients were not overdosed and therefore at more risk (Mercadante et al., 2002). In contrast, in a subsequent study, after intravenous titration patients were put on oral morphine regularly at a dose approximately equal to the intravenous requirement, given every 4 h, using a ratio 1:1 (Harris et al., 2003), despite existing recommendations, based on level 3 evidence, which suggest a ratio of 1:2–1:3 (Hanks et al., 2001). This could be attributed to the way of titration, diluted in time, which artificially increased the intravenous opioid requirements, in comparison with the subsequent real opioid need. The use of lipophilic drugs such as fentanyl would result in a faster titration, as peak plasma levels and passage through the blood–brain-barrier could be obtained early. Intravenous fentanyl was administered for emergency situations as a bolus dose over 10 s, in a four-step protocol, starting with 10% of the intravenous equivalent doses of morphine (using a ratio of
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1:100). All patients responded successfully within a mean of 11 min with mean intravenous fentanyl doses of 2.14 mg (0.6–5.25 mg). This treatment was intended as an emergency intervention, rather than to predict the future opioid dosage (Soares et al., 2003). Acute cancer-related pain has been treated with fentanyl administered by continuous intravenous infusion in combination with PCA, and then switched to transdermal fentanyl at a doses equivalent to the rate of the final continuous intravenous infusion, once stable pain relief has been achieved. The infusion rate was decreased by 50% 6 h after application of the fentanyl patch and then discontinued 6 h after. Demand boluses of IV fentanyl were available by PCA during the 24 h after patch application. This study demonstrated that conversion from intravenous to fentanyl TTS can be accomplished effectively using a 1:1 conversion ratio and a two-step taper of the intravenous infusion over 12 h (Kornick et al., 2001). 2. Conclusion A stepwise approach to the use of analgesic drugs is essentially a framework of principles rather than a rigid protocol. This allows considerable flexibility in the choice of specific drugs and modalities of approach. Morphine titration is a safe and effective method to find the appropriate dose. In patients who were previously receiving opioids for moderate pain, an initial starting dose of 60 mg of oral morphine equivalents, both as immediate release and sustained release formulations, and rescue doses to titrate the dose, may allow obtaining effective pain control within 24–48 h. Strict observation and frequent dose adjustments should be provided. Further dose adjustments according to the daily consumption allows the control of pain in most patients, who are responsive to morphine. Such initial doses of morphine or equivalent doses of other opioids, like transdermal fentanyl, are not advisable in opioid-naive patients to avoid step 2 drugs. Nevertheless, the use of lower starting doses of morphine can be a meaningful and effective method to titrate the dose for these patients. Dose increments of opioids, 30–50%, are suggested in the presence of worsening analgesia during the course of illness, with the limitation of the occurrence of adverse effects. Parenteral administration of opioids may help accelerating dose finding or even improving the analgesic response. A poor balance of analgesia and adverse effects intensity suggests a careful re-evaluation of medication and the pain syndrome to reassume the global response to the opioid used. In patients with severe pain on an emergent basis, a intravenous morphine titrated against the effect, can be safely titrated rapidly in an appropriate setting.
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Mystakidou K, Befon S, Tsilika E, et al. Use of fentanyl TTS as a single opioid for cancer pain relief: a safety and efficacy trial in patients naive to mild of strong opioids. Oncology 2002;62: 9–16. Mystakidou K, Tsilika E, Kouloulias V. Long-term cancer pain management in morphine pre-treated and opioid naive patients with transdermal fentanyl. Int J Cancer 2003;107:486–92. Peng Y, Sun W. Mini-dose titration of the transdermal fentanyl patch – a novel approach by adjusting the area of absorption. J Pain Symptom Manage 2005;30:7–8. Portenoy RK, Foley KM, Inturrisi CE. The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain 1990;43:273–86. Portenoy K, Southam MA, Gupta SK, Lapin J, Layman M, Inturrisi CE, et al. Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics. Anesthesiology 1993;78:36–43. Radbruch L, Loick G, Schulzech S, Beyer A, Lynch J, Stemmler M, et al. Intravenous titration with morphine for severe cancer pain: report of 28 cases. Clin J Pain 1999;15:173–8. Soares LG, Martins M, Uchoa R. Intravenous fentanyl for cancer pain: a fast titration protocol for the emergency room. J Pain Symptom Manage 2003;26:876–81. Tawkfik MO, Bryuzgin V, Kourteva G. Use of transdermal without prior opioid stabilization in patients with cancer pain. Curr Med Res Opin 2004;20:259–67. van Seventer R, Smit JM, Schipper RM, Wicks MA, Zuurmond WWA. Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain. Curr Med Res Opin 2003;19:457–69. Vielvoye-Kerkmeer A, Mattern C, Uitendaal M. Transdermal fentanyl in opioid-naive cancer patients: an open trial using transdermal fentanyl for the treatment of chronic cancer pain in opioid-naive patients and a group using codeine. J Pain Symptom Manage 2000;19:185–92.
Review
Opioid titration in cancer pain: A critical review Sebastiano Mercadante
*
Anesthesia and Intensive Care Unit & Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Palermo, Italy Palliative Medicine, Department of Anesthesia, Intensive Care and Emergencies, University of Palermo, Italy Received 4 November 2006; received in revised form 22 December 2006; accepted 15 January 2007 Available online 28 February 2007
Abstract Initiation of therapy with strong opioids is a challenging phase to obtain the maximum benefit and to gain the patient’s compliance. The approach could be different, depending on the clinical situation and type of opioid regimen. Substantially, the need to titrate the dose of strong opioids emerges in different conditions: (a) in opioid-naive patients who require an opioid treatment; (b) in patients no longer responsive to weaker drugs requiring strong opioids; (c) in patients already receiving strong opioids requiring higher doses because of an increase in pain intensity or a new acute pain problem; (d) in patients who are severely suffering and need an intensive as well as rapid intervention, due to previous persistent undertreatment. Whilst there is a vast literature confirming the effectiveness of most opioid drugs for the treatment of chronic pain, there is a lack of information regarding opioid titration. This review assesses the principal titration methods and outcomes regarding the different opioid drugs and their modalities of administration, in different clinical contexts. Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Cancer pain; Opioid titration
1. Introduction Most cancer pain responds to pharmacological measures, and successful treatment is based on the administration of analgesics, according to the WHO analgesic ladder. Strong opioids should be used if pain is unrelieved by weak opioids or is severe at the outset. The regular use of morphine by mouth has done much to improve the management of pain in advanced cancer. Oral morphine is conventionally the opioid of choice, because of its established effectiveness, availability, familiarity to physicians, simplicity of administration, and relative cost. However, information regarding alternative opioids is improving. Some of these drugs may be useful for their specific physical and pharmacological *
Tel.: +39 091 6806521; fax: +39 091 6806110. E-mail address: [email protected].
characteristics and are currently used with outcomes similar to those observed with the use of morphine (Hanks et al., 2001). From a clinical point of view, the use of different opioids with specific characteristics and modalities of administration, may require different approaches to face a particular clinical situation. Initiation of opioid therapy is a delicate and challenging phase to obtain the maximum benefit and to gain the patient’s compliance. This means that a careful balance between a rapid pain control and the possible development of adverse effects is imperative. There are different clinical scenarios which may require different approaches. One is represented by opioid-naive patients who require an opioid treatment. Another clinical situation is represented by patients who are no longer responsive to weaker drugs and require strong opioids. Moreover, patients already receiving strong opioids may require higher doses during the course of disease,
1090-3801/$32 Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2007.01.003
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due to an increase in pain intensity or a new acute pain problem. Finally, some patients who are severely suffering, often due to undertreatment, may need a more intensive and rapid intervention. The latter condition will require higher levels of expertise and more complex approaches. The aim of this article was to critically review the principal titration methods and outcomes described in literature regarding the different opioid drugs and their modalities of administration, also taking into account the different clinical contexts. Comments included in this review should be considered as personal opinions and are open to further criticism and discussion. 1.1. Search strategy and selection criteria Data for this review were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using the search term ‘‘opioid titration’’. Abstracts and reports from meetings were also included. Only articles published in English between 1980 and 2005 were included. Additional hand searching was performed from pain and palliative care journals, as well as personal files. From the reference lists, key textbooks and previous reviews were searched for additional studies. Considering the predictable poor homogeneity of patients, the different purposes and clinical settings, no attempt to perform a meta-analysis was done. Papers were also re-ordered according to the different clinical contexts to have a more didactic overview, and then were critically reviewed. 1.2. Opioid titration in opioid-naive patients Opioid-naive patients receiving non-opioid analgesic drugs unsuccessfully may have moderate-severe pain. According to WHO guidelines patients should be started with opioids for moderate pain, including codeine, tramadol, or dextropropoxyphene. The role of ‘‘so called weak opioids’’ in the treatment of moderate cancer pain has been questioned, and it has been speculated that the second step of analgesic ladder could be omitted (Eisenberg et al., 1994). Opioids for moderate pain have been compared with morphine. In opioid-naive-patients, a more favorable balance between side effects and analgesia occurred when step two opioids were compared to low doses of morphine (Mercadante et al., 1998a,b; Grond et al., 1999). However, comparison was based on doses of morphine which could be considered relatively high in opioidnaive patients, who are at higher risk of developing adverse effects. Recent studies have assessed the use of strong opioids in opioid naive patients skipping the second step drugs. Starting doses of 0.6 mg/day of fentanyl have been used
successfully (Mystakidou et al., 2001; Mystakidou et al., 2002; Mystakidou et al., 2003; Mystakidou, 2004). According to this information it should be assumed that doses of 0.6 mg/day of fentanyl TTS can be safety used in opioid-naive patients. Despite such optimistic outcomes, these findings are unrealistic. This is unlikely to occur in the raw clinical setting, due to the high risk of producing adverse effects and reducing patient’s compliance. This observation was confirmed in a study where fentanyl TTS used at doses of 0.6 mg/day, was better tolerated by patients receiving codeine rather than in opioid-naive patients, who stopped the treatment prematurely in 21% of cases (Vielvoye-Kerkmeer et al., 2000). In another study comparing oral morphine and fentanyl TTS, a high percentage of patients among opioid-naive patients starting strong opioids (fentanyl TTS 0.6 mg/day or oral morphine 60 mg/day), developed moderate-to-severe adverse effects. Of interest, only about half patients completed the four week period of observation (van Seventer et al., 2003). Similarly, opioid-naive patients receiving 0.6 mg/day of fentanyl TTS developed relevant adverse effects in comparison with patients previously treated with opioids, and were more likely to withdraw because of adverse effects (Tawkfik et al., 2004). The sequential treatment proposed by WHO has been compared with strong opioids used as the first step. Treatments appeared equally effective, although the group treated with opioids first had a better pain relief and patients’ satisfaction, and a minor number of therapeutic interventions. However, nausea was more frequently reported. Only 50% of patients in the control group needed strong opioids in doses similar to those used in patients who received strong opioids first (Marinangeli et al., 2004). Unfortunately, the initial doses of strong opioids were not mentioned, making evaluation of data difficult, although among the drugs is reported fentanyl, of which the minimal existing dose in Italy is 0.6 mg/day. A similar approach has been recently proposed, showing that strong opioids may provide advantages over the traditional strategy in terms of the percentage of days with worst pain, but also require careful management of side effects (Maltoni et al., 2005). Interestingly, patients who started morphine 60 mg/day, a dose which is more or less equivalent to fentanyl 0.6 mg/day, after receiving weak opioids, developed adverse effects and titration was delayed in about 25% of patients. This occurred despite patients were not opioid-naive (Klepstad et al., 2000a,b). It is likely that opioid-naive patients are more susceptible to adverse effects related to relatively high opioid doses. Morphine used at very low doses in opioid-naive patients may offer different advantages, including a greater tolerability during dose titration while providing
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effective analgesia. The rationale was to replace opioids commonly used for moderate pain with morphine used in doses equivalent to the range of activity of second step drugs, commonly prescribed in clinical practice. In a recent trial, titration started with doses of 10– 15 mg/day of morphine, was well tolerated even by older patients, who could be effectively titrated reporting similar effects to those found in adults. Mean doses of less than 45 mg/day of morphine were achieved four weeks after, which means that initiating with 60 mg/day would translate in overdosing (Mercadante et al., 2006a,b). Similar data were reported with minimal doses of oxycodone (Koizumi et al., 2004). Some authors suggested to use an occlusive dressing between the fentanyl patch and the skin to reduce the rate of absorption, providing a dose of 0.3 mg/day and doubling the duration of effect (Peng and Sun, 2005). This method seems to be intuitively unreliable. No scientific data is available in literature with a patch of 12.5 mcg/h. According to this data, opioids for moderate pain may still have a role in the second step of the analgesic ladder. The role of strong opioids is less defined. It is likely that the doses of 60 mg oral morphine equivalents in opioid-naive patients, may produce strong analgesia but are likely to induce more consistent adverse effects. Thus, such doses should be reserved to patients who have received opioids for moderate pain unsuccessfully (see below). Alternately, if the intention is to avoid step 2, morphine or oxycodone titration should be started at the lowest level, as many patients may have a good response with low initial doses of morphine. Doses of 25 mcg/h of transdermal fentanyl (0.6 mg/day), corresponding to a large range of oral morphine (about 60 mg/day), should not be recommended for opioidnaive-patients. In some countries a 12 mcg/h patch is now available, but no scientific data about the use of this dosage has been reported yet. 1.3. Opioid titration in patients who have received weak opioids unsuccessfully 1.3.1. Oral opioids The use of morphine in patients switched from weak opioids has no major influence on aspects of healthrelated quality of life, other than pain (Hwang et al., 2003; Klepstad et al., 2000a,b; Mercadante et al., 2006a,b). The simplest method of dose titration has been provided by EAPC recommendations. During dose titration it is preferable to use an immediate release formulation of morphine that has a rapid onset and a predictable effect. A dose of immediate-release oral morphine is given every 4 h and the same dose for breakthrough pain given as often as required. Patients changing from a weak opioid will usually start with 10 mg every 4 h (60 mg/day). A rescue dose of 16% of
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the total daily dose of the used opioid is commonly prescribed. The total daily dose of morphine should be reviewed daily, based on the assumption that steady state of morphine is reached in about 24 h. If pain returns before giving the regular dose, the regular dose should be increased (Hanks et al., 2001). This approach is suggested by pharmacological observations: peak plasma concentration usually occurs within the first hour after administration of an immediate release formulation of morphine, while controlled release morphine tablets produce delayed peak plasma concentration, after 2–4 h. Recent studies tried to support this approach. A morphine titration schedule has been used in a prospective case series involving 40 patients. Patients receiving rescue ketobemidone were started with immediate release oral morphine 60 mg daily and the dose was increased 33–50% each day (60 mg, 90 mg, 120 mg, 180 mg/day) to obtain satisfactory pain relief. The mean daily morphine dose after titration was 97 mg and the time needed for stopping titration was 2.3 days. Dose titration was postponed in nine patients due to sedation. Constipation and nausea significantly increased after starting morphine. More than 80% of patients were satisfied with the pain treatment (Klepstad et al., 2000a,b). However, at these low levels of pain intensity any judgement is disputable: pre-titration level pain intensity using ketobemidone as a rescue drug was not relevant, and pain intensity passed from a mean pre-titration value of 32 mm (which could be considered by most clinicians as a tolerable level of pain intensity) to 16 mm on a visual analogue scale, at the end of titration. Despite the large use of opioids in cancer pain management, however, these recommendations are flawed by the lack of objective data. The delay in achieving peak plasma concentrations, the attenuation of peak plasma concentrations, and the long duration of action potentially make the use of sustained-release preparations for initial dose titration more difficult. This EAPC statement was contradicted by a recent controlled-randomized, double-blind, double-dummy study comparing titration with immediate-release morphine given 4hourly with titration with sustained-release morphine given once daily. Morphine dose titration was concluded within 2.1 and 1.7 days, respectively (Klepstad et al., 2003). This means that the preliminary use of immediate-release morphine is not strictly necessary. However, these data should be interpreted with caution, as pretitration pain intensity was really mild, as in the previous study (Klepstad et al., 2000a,b), suggesting a floor effect. Thus, no conclusion about the preference of immediate or sustained release can be drawn. It is important to guarantee patients with an adequate dose of immediate release formulation as needed during the dose titration, independently from the use of regular
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immediate or sustained release formulation used as a basal opioid regimen. 1.3.2. Transdermal opioids The use of trandermal (TTS) drugs has been increasing in the last decade, particularly fentanyl TTS. The initial dose finding with fentanyl TTS is often unsatisfactory in patients with unstable pain, as some patients may require early and frequent dose increments to achieve pain control, and steady-state plasma concentrations are delayed in comparison with oral opioids, due to the peculiarity of this delivery system. According to these observations, fentanyl TTS should not be indicated for opioid titration and should be recommended after pain is controlled by other opioids (Hanks et al., 2001). Nevertheless, there are several studies reporting the use of fentanyl TTS in these circumstances. A simple and logical approach could be that patients are provided with rescue medication and encouraged to take this, especially in the first 48–72 h after patch application. Doses can be re-calculated before the next application (Donner et al., 1996). In ambulatory patients who failed an adequate trial of opioids used for moderate pain, fentanyl TTS started at doses of 0.6 mg/day was safe, also providing a reduction in pain score over the 7day study period, and a progressive decrease in rescue medications (Hammack et al., 1996). Alternative approaches have been suggested, including day-to-day titration to initiate fentanyl TTS. The minimal dose was 0.6 mg/day, which was started in a miscellanea of patients, including opioid-naive patients, patients receiving weak opioids, or strong opioids in the range of 0–88 mg of oral morphine equivalents. Titration was repeated every day with an additional patch, until adequate pain control was achieved, unless adverse effects occurred. Morphine was used as a rescue medication. Satisfactory analgesia was achieved within 24–48 h. About half of patients needed dose increases, opioidnaive patients requiring fewer dose increments than opioid-treated patients (Korte et al., 1996). Despite the favorable outcome reported by authors, adverse effects were of concern, for different reasons, in three patients. In vulnerable outpatients, who do not have intensive monitoring, this procedure could be risky, as analgesic serum concentration may not be achieved in some patients before 24 h, due to the large interindividual variability (Portenoy et al., 1993). 1.3.3. Parenteral opioids Opioids, given parenterally, may produce fast and effective plasma concentrations in comparison with oral or transdermal opioids. This means that dose stabilization can be achieved in a shorter period of time. In a comparative study oral morphine was titrated, according to EAPC recommendations, with 5–10 mg
every 4 h, and the same dose was provided as needed, while the intravenous group received boluses of 1.5 mg every 10 min. Subsequently, after finding the effective dose by titration, the total daily dose was converted to oral morphine (Harris et al., 2003). As expected, satisfactory pain relief at 1 h was achieved by most patients in the intravenous group, in comparison with the oral group, while no differences in pain intensity and adverse effects were found 24 h after. The time course reflects the characteristics of the routes, intravenous being faster because of the short lag-time between injection and effect (initial 3 min, peak 30 min) in comparison with oral dosing (initial 15–30 min, peak 45– 60 min). This kind of advantage is evident in the first hours after administration, when more intravenous boluses were allowed, rather than 24 h after, when repeated dosing of oral morphine in both arms provide similar effects. The main potential of patient-controlled analgesia (PCA) lies in the individual titration of the analgesic dosage by providing rapid pain relief for a wide range of requirements. Patients with severe cancer pain and insufficient analgesia with step 2 analgesic drugs were titrated with morphine delivered intravenously by a PCA pump set with a bolus dose of 1 mg, lock-out time of 5 min, and hourly maximum dose of 12 mg (Radbruch et al., 1999). Significant pain relief was achieved within 24 h with mean doses of 32 mg/day of intravenous morphine, which were then converted to a mean of 139 mg equivalent of oral morphine (including PCA doses). In a minority of patients who were assessed with this aim, the mean time to achieve sufficient analgesia was 6 h. Adverse effect intensity was mild, mostly present before starting the study. In conclusion dose titration with oral opioids, particularly with short-onset drugs such as morphine, may provide adequate pain relief in about 48 h in most patients. Although the majority of studies regarded morphine, oxycodone and hydromorphone, which have a similar pharmacokinetic profile, are expected to produce a similar outcome. According to available data, one could also argue that most opioids, even long-acting preparations, can be safety and effectively used, if doses as needed are provided to make appropriate dose adjustments until stabilization is achieved. Similarly, transdermal drugs may also be effective, if combined with adequate measures, able to cover the first 24 h, with short-onset opioids administered as needed. Long-acting opioids, both orally or transdermally, should be started at low doses and effects should be carefully monitored before any change in dose. Parenteral opioids may accelerate the timing for achievement of adequate pain relief. The daily dose could subsequently be converted to the oral route. The common parenteral-oral ratio for morphine is 1:2.5 (Hanks et al., 2001).
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1.4. Patients who are receiving strong opioids and require dose adjustment 1.4.1. Oral and transdermal opioids With inadequate pain relief, opioid doses have to be increased stepwise, that is with a dose increase of 33– 50% every 24 h (Hanks et al., 2001). If pain is responsive to the opioid used, further dose increments often result in enhanced analgesia. This approach can require several days or even weeks until adequate pain relief is obtained. Several studies have assessed the opioid response in time using an escalation index, which provides a simple tool to record the need of opioid escalation in time (Mercadante et al., 1999). For example the opioid escalation index of methadone is lower when compared with that of morphine (Mercadante et al., 1998a,b). The occurrence of adverse effects may limit the dose escalation. This process is based on an individual response which depends on several factors (Portenoy et al., 1990). The opioid response may change in time, due to the intervention of numerous factors. This issue is beyond the aim of the present article. 1.4.2. Parenteral opioids Data on the use of parenteral opioids in patients requiring increasing doses of oral or transdermal opioids is lacking. In one study, the efficacy of the start of parenteral opioids was prospectively assessed in patients who failed with oral or transdermal opioids. A subcutaneous infusion of different opioids was started on 50– 70% of the equianalgesic dose, a median of 80 mg/day of intravenous morphine equivalents, and rescue doses were offered as needed (Enting et al., 2002). Doses were titrated up to 135 mg of intravenous morphine equivalents obtaining a good pain control in more than 50% patients within 48 h. Of interest, no significant changes in adverse effects was evidenced. The variability in the second evaluation time (1–27 days), when an important improvement was seen in 71% of patients, make data on follow-up difficult to evaluate. 1.5. Emergency treatments for patients with severe pain Differently from most cancer population, which may have moderate pain intensities and require simple and soft titration schedules, cancer pain may present as an emergency. Emergency is commonly defined in accordance with severity (pain intensity of 8/10 or greater on a numeric rating scale), duration, and progression over time. Acute severe pain requires rapid application of powerful analgesic strategies and aggressive treatment, which are distinct from chronic management techniques. Patients who present with a pain emergency may receive a regular treatment which has been rapidly loosing efficacy or may have important changes of pain causes. Alternately, patients may present excruciating
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pain of weeks or months duration, largely undertreated. Often they do not receive any opioid. As their optimal dose is unpredictable, a traditional titration could take several days and will result in unuseful suffering for patients. In these circumstances, it could be advisable to expedite opioid titration using the fastest methods. Intravenous titration has been found to be more rapid than oral titration (Harris et al., 2003). In a randomized clinical trial subcutaneous morphine titration required more time and higher doses than intravenous titration in patients with exacerbation of cancer pain (Elsner et al., 2005). Boluses of intravenous and subcutaneous morphine were given every 5 0 and 30 0 , respectively. Doses were proportional to the previous daily opioid consumption and were 2 mg and 10 mg, respectively, for patients receiving less or more than 120 mg of oral morphine equivalents. It is likely that authors assumed that after 30 min doses of intravenous morphine allowed in five boluses of 2 mg would be equivalent to the dose administered by subcutaneous route (10 mg) reaching a peak at the same time of that presumed for subcutaneous route. Titration stopped after patients achieved similar pain intensity in the two groups, within a mean of 53 and 77 min, respectively, and percentage of patients with 30% and 50% pain relief was higher in the intravenous group, despite having initial higher scores of pain intensity. A factor of 1:6.6 for the intravenous titration dose to the daily requirement of oral opioids was found four days after titration. However, this factor was only 3.7 in the subcutaneous group. As data for calculation was made for a limited number of patients, no conclusion can be drawn. As expected, 24 h after and later the results regarding pain relief and adverse effects were comparable. Of interest, as reported in other studies, some symptoms, such nausea, may improve rather than worsen after pain control is achieved. From a pharmacokinetic point of view, total availability and rapid effective plasma concentrations, required for a timely intervention are best achieved with the intravenous route. Titration with intravenous morphine may provide fast and efficient pain relief, also providing information about the amount of opioid necessary for a subsequent treatment. The use of intravenous morphine for these purposes is not new, as more than twenty years ago titration with very high doses of intravenous morphine had already been reported to be effective and safe even in outpatients (Adams et al., 1984; Citron et al., 1984) and more recently in particular settings, at home and in children (Elsner et al., 2000; Mollet and Piquard-Leandri, 1999). However, physicians have been reluctant in using intensive procedures because of the possible risks and poor familiarity with the intravenous route. In recent years a growing interest in palliative care and skills in other routes of administration prompted physicians to face more aggressive
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measures to improve the efficacy of analgesic interventions in some difficult conditions. Different approaches, while similar, are different as intensity, rapidity and safety issues are supported by different rationale and pharmacokinetic strategies. In a pilot study of patients receiving high doses of oral morphine equivalents (median 1530 mg) unsuccessfully, 10–20 mg of intravenous morphine were administered over 15 min and the dose doubled every half hour until pain was controlled (5 or less on a numeric rating scale from 0 to 10). Satisfactory relief of excruciating pain was achieved within a mean of 90 min. Maintenance analgesia was then instituted according to the amount of boluses administered (Hagen et al., 1997). In a retrospective analysis of a large number of patients reporting a pain intensity of at least 5/10, repeated boluses of 1.5 mg of morphine, intravenously every 10 min, were given to an end-point of either total pain relief or drowsiness. This approach provided total pain relief in 79% of patients, with a dose range of 1.5–15 mg of morphine for most patients. About 1/3 of patients reported consistent adverse effects, 32% of patients were drowsy at the end of the procedure, and in 10% this was the indication to stop titration. However, adverse effects were never troublesome (Kumar et al., 2000). This approach was proportional to the entity of the problem, as patients with a not severe pain intensity were also included. Familiarity with opioid pharmacokinetics and pharmacodynamics and clinical experience are helpful in selecting the most appropriate analgesic strategy. Morphine administered as an intravenous bolus exerts an effect within few minutes. The time of peak blood level and the time to peak analgesia have a hysteresis, corresponding to the delay in passing the blood–brain barrier, due to the low lipid solubility of morphine. Thus, the end-point should not be complete pain relief, but the trend observed after some minutes, as it is expected that the major effect will be apparent with a certain delay. On the other hand, repeated small boluses, while less effective, can be confounding, as multiple pharmacokinetic curves may overlap. For example, from the series above described, the maximum bolus of morphine was 34.5 mg. This means that these patients received 23 boluses of 1.5 mg every 10 min in 215 min. In the meantime most of the initial amount of morphine boluses are largely eliminated, so that the real effective dose is difficult to determine. This can explain the intravenous-oral ratio of 1:1 used by authors for oral conversion. A method of rapid titration with intravenous morphine for severe cancer pain and immediate oral conversion was explored using a more intensive approach (Mercadante et al., 2002). Intravenous boluses of 2 mg every 2 min were given to patients presenting severe pain, graded 7/10 or more on a numeric pain scale 0– 10. The target to stop titration was not the pain relief,
rather patient’s detection of significant analgesia or the occurrence of severe adverse effects, regardless of the previous analgesic treatment. The total dose administered was assumed to last approximately 4 h and was then computed for 24 h. The intravenous daily dose was converted to oral morphine using a ratio of 1:3. In patients requiring high doses of intravenous morphine or frail patients, a more prudent ratio was used (1:2, that is 120 mg/day in the previous example). Oral dosing was recalculated on a daily basis, according to the global opioid consumption. A significant decrease in pain intensity was achieved in a mean of 9.7 min with a mean dose of 8.5 mg of intravenous morphine. Patients were discharged within a mean of 4.6 days, with a mean dose of oral morphine of 131 mg/daily and acceptable pain control. Thus, the total amount of morphine required during intravenous titration may be the basis to determine an adequate dose of an oral sustained release formulation to facilitate discharge at home. No immediate significant adverse effects were reported after titration with intravenous morphine. It is important to consider the lag-time between the initial effect (within minutes) and peak effects (about half-hour) of intravenous morphine, due to a delay of morphine in passing the brain barrier. Therefore, the target of the decisionmaking process is the trend of pain intensity between the bolus intervals, rather than a complete pain relief. Careful observation and judicious bedside clinical assessment are the best guides for further intervention. This does not result in an increased risk. Apart from the intensive care setting, where the study was performed, assuring resuscitation expertise, experimental studies have suggested that the presence of pain makes the occurrence of respiratory depression unlikely (Borgbjerg et al., 1996). It is interesting to note that in this latter study no patient required a decrease in the oral morphine dose after conversion, confirming that patients were not overdosed and therefore at more risk (Mercadante et al., 2002). In contrast, in a subsequent study, after intravenous titration patients were put on oral morphine regularly at a dose approximately equal to the intravenous requirement, given every 4 h, using a ratio 1:1 (Harris et al., 2003), despite existing recommendations, based on level 3 evidence, which suggest a ratio of 1:2–1:3 (Hanks et al., 2001). This could be attributed to the way of titration, diluted in time, which artificially increased the intravenous opioid requirements, in comparison with the subsequent real opioid need. The use of lipophilic drugs such as fentanyl would result in a faster titration, as peak plasma levels and passage through the blood–brain-barrier could be obtained early. Intravenous fentanyl was administered for emergency situations as a bolus dose over 10 s, in a four-step protocol, starting with 10% of the intravenous equivalent doses of morphine (using a ratio of
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1:100). All patients responded successfully within a mean of 11 min with mean intravenous fentanyl doses of 2.14 mg (0.6–5.25 mg). This treatment was intended as an emergency intervention, rather than to predict the future opioid dosage (Soares et al., 2003). Acute cancer-related pain has been treated with fentanyl administered by continuous intravenous infusion in combination with PCA, and then switched to transdermal fentanyl at a doses equivalent to the rate of the final continuous intravenous infusion, once stable pain relief has been achieved. The infusion rate was decreased by 50% 6 h after application of the fentanyl patch and then discontinued 6 h after. Demand boluses of IV fentanyl were available by PCA during the 24 h after patch application. This study demonstrated that conversion from intravenous to fentanyl TTS can be accomplished effectively using a 1:1 conversion ratio and a two-step taper of the intravenous infusion over 12 h (Kornick et al., 2001). 2. Conclusion A stepwise approach to the use of analgesic drugs is essentially a framework of principles rather than a rigid protocol. This allows considerable flexibility in the choice of specific drugs and modalities of approach. Morphine titration is a safe and effective method to find the appropriate dose. In patients who were previously receiving opioids for moderate pain, an initial starting dose of 60 mg of oral morphine equivalents, both as immediate release and sustained release formulations, and rescue doses to titrate the dose, may allow obtaining effective pain control within 24–48 h. Strict observation and frequent dose adjustments should be provided. Further dose adjustments according to the daily consumption allows the control of pain in most patients, who are responsive to morphine. Such initial doses of morphine or equivalent doses of other opioids, like transdermal fentanyl, are not advisable in opioid-naive patients to avoid step 2 drugs. Nevertheless, the use of lower starting doses of morphine can be a meaningful and effective method to titrate the dose for these patients. Dose increments of opioids, 30–50%, are suggested in the presence of worsening analgesia during the course of illness, with the limitation of the occurrence of adverse effects. Parenteral administration of opioids may help accelerating dose finding or even improving the analgesic response. A poor balance of analgesia and adverse effects intensity suggests a careful re-evaluation of medication and the pain syndrome to reassume the global response to the opioid used. In patients with severe pain on an emergent basis, a intravenous morphine titrated against the effect, can be safely titrated rapidly in an appropriate setting.
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