REVIEW For reprint orders, please contact: [email protected]
Versatility of different pharmaceutical formulations of hydromorphone in the management of severe cancer pain and pain in palliative care
Practice Points
Katri E Clemens*1 & Rudolf Likar2 Opioids are the treatment of choice in severe chronic cancer pain and severe pain in palliative care, in
elderly patients and patients with multimorbidity. Until recently morphine was the gold standard for the treatment of severe cancer pain and nonmalignant
pain according to current WHO guidelines (step III). Several opioids, including hydromorphone, provide a suitable alternative treatment option. Now, morphine, hydromorphone and oxycodone are regarded as equivalent in the 2012 evidence-based recommondations from the European Association for Palliative Care. Hydromorphone is available in several formulations: sustained-release formulations (capsules for
twice-daily use, twice-daily tablets and once-daily tablets), immediate-release formulations (capsules) and injectable solutions (for intravenous, subcutaneous, intrathecal or epidural application). The versatility of different hydromorphone formulations provides the physician with the opportunity and
flexibility to adapt the route of administration to the individual patient’s situation. The availability of hydromorphone as sustained-release, immediate-release and parenteral formulations
renders this strong opioid particularly suitable for consistent opioid administration with predictable substance release. This may reduce the need to change opioids.
SUMMARY The management of severe pain situations requires therapeutic expertise in dealing with changes in pain intensity, analgesic limitations and individual patient needs. Opioids are the treatment of choice in severe pain. The availability of a broad range of opioids and formulations refined the options for improved pain treatment with a specific substance. These may include oral formulations, injectables and other applications suitable for different patient needs. Moreover, variable drug concentrations are most useful in clinical practice. This article briefly reviews the versatility of different hydromorphone formulations in the management of severe pain in palliative care and cancer. Limiting strong opioid treatment with one opioid substance in different formulations (adjuvants if necessary), according to varying requirements of patients, would be eligible for achieving a well-tolerated and effective pain therapy. Its versatility renders hydromorphone suitable for consistent opioid administration with predictable substance release, and may thus contribute to reducing the need for opioid change. Clinic for Palliative Medicine, MediClin, Robert Janker Klinik, Villenstr, 4–8, D-53129 Bonn, Germany Klinikum-Klagenfurt am Wörthersee, Department of Anesthesia, Feschnigstr 11, A-9020 Klagenfurt am Wörthersee, Austria *Author for correspondence: Tel.: +49 228 5306 301; [email protected] 1 2
10.2217/PMT.13.26 © 2013 Future Medicine Ltd
Pain Manage. (2013) 3(5), 369–375
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Review Clemens & Likar One of the most important medical goals in caring for elderly, multimorbid and incurable patients is to alleviate pain and, thus, optimize quality of life. It is only a minority of pain patients whose pain cannot be adequately alleviated, for example, by reason of intolerable side effects or development of antinociceptive tolerance – that is, most pain situations can be controlled by appropriate analgesic measures. From the medical perspective, the aging patient is characterized by considerable changes in physiology, for example, reduced renal function, reduced muscle mass, increased adipose tissue, but also a deterioration in cognitive abilities. Any pharmaceutical approach to the treatment of a particular disease has to consider these possible changes and their respective impact on elimination, plasma levels, drug interactions and impaired compliance [1]. Approximately 20–50% of patients with early-stage cancer, and 50–95% of patients with a progressive stage of cancer, experience pain [2,3]. According to WHO recommendations, strong opioids are the medication of choice for severe cancer pain [4]. A precondition for an effective therapy is the right choice of compound, the dose, time intervals and route of administration. Besides morphine, still referred to as the first-choice opioid in the WHO recommendations, hydromorphone was mentioned, until recently, only as a possible alternative, as well as other strong opioids like methadone, oxycodone or buprenorphine. Meanwhile, the WHO treatment guidelines are due to be updated, to incorporate progress that has been made in clinical experience with different formulations of opioids in the treatment of non malignant and cancer pain, and questioning whether morphine should still be referred to as the ‘gold standard’ [101,102]. The 2012 European Association for Palliative Care (EAPC) guidelines now recommend hydromorphone and oxycodone as equivalent to morphine as the firstchoice step III opioid for moderate-to-severe cancer pain, and methadone as a consideration of alternative [5,6]. This article provides an overview of available data relating to the versatility and resulting clinical benefit of pharmaceutical formulations of hydromorphone (WHO step III opioid) for the management of cancer pain and the treatment of pain of other etiology in palliative care, in elderly patients and patients with multimorbidity.
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Methods The authors searched databases and handsearched relevant journals to identify randomized and nonrandomized controlled trials assessing the analgesic effect of hydromorphone for cancer pain. The authors continuously searched, read and selected current literature (search terms were opioids, hydromorphone, cancer pain and palliative care) concerning pain management in cancer patients and palliative care patients, mainly using PubMed, MEDLINE, Cochrane Central Register of Controlled Trials Databases and other standard electronic literature databases from 1980 up to December 2011. Due to the special relevance in this patient group, information gathering focused on strong opioids. Only original clinical studies comparing hydromorphone (oral and parenteral applications) with other strong opioids or evaluating the efficacy and safety of a hydromorphone formulation were selected. Reviews and meta-analyses were excluded. Results Out of the initial 216 papers generated using the above mentioned search terms, the authors selected 15 original clinical studies for a closer analysis: seven randomized controlled trials, two randomized crossover studies, three uncontrolled retrospective studies, one uncontrolled prospective study, one nonrandomized prospective study and one clinical study. Authors, basic data and the design parameters are reported in Table 1. Hydromorphone
Hydromorphone, a semi-synthetic opioid, has opioid-agonistic properties [7]. The generally accepted conversion ratio of orally administered hydromorphone to morphine is a factor of 7.5 [8,9]. However, a variability in equianalgesic tables has been published. The bases of these tables, such as study design and population, are often not specified and they do not verify if equivalences were determined by single dose or at steady state. Furthermore there are interindividual differences in equivalents [10]. Taking the conversion ratio of the original tables into account, the analgesic efficacy of hydromorphone and morphine are comparable [9]. Wirz et al. found morphine with a higher rate of side effects (nausea, emesis and constipation) than hydromorphone [11]. Hydromorphone has no ceiling effect; it can be uptitrated according to the pain level without
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Hydromorphone in cancer pain & palliative care
Review
Table 1. The basic data and design parameters of the analyzed studies. Study (year)
Study design
Patients Administration route/formulation and compared (n) opioids
Ref.
Babul et al. (1995) Bruera et al. (1996) Chang et al. (2006) Clemens and Klaschik (2007) Clemens and Klaschik (2007) Hagen and Babul (1997) Hanna et al. (2008) Hays et al. (1994) Lee et al. (2001) Moriarty et al. (1999) Moulin et al. (1991) Thwaites et al. (2004) Vallner et al. (1981) Vashi et al. (2005)
Clinical study Randomized controlled trial Randomized controlled trial Retrospective study
2 95 198 81
Oral controlled-release H Oral H: extended-release vs immediate-release Intravenous H vs intravenous M Oral H vs transdermal F
[36]
[34]
Nonrandomized prospective study
11
Oral H and M
[35]
Randomized controlled trial
44
Oral H vs oral O
[41]
Randomized controlled trial Randomized controlled trial Uncontrolled retrospective study Randomized controlled trial Randomized controlled trial Uncontrolled retrospective study
200 48 55 100 20 48
[40] Oral H vs oral M [42] Oral H: extended-release vs immediate-release [17] Oral extended-release H [9] Oral H vs oral M Continuous parenteral H (intravenous/subcutaneous) [33] Continuous parenteral H (intravenous/subcutaneous) [18]
6 24, 26, 26 148
Intravenous H vs oral H Oral extended-release H
[32]
Oral extended-release H
[30]
Randomized two-way crossover pilot study Two single-dose, randomized crossover studies and one multiple-dose, two-way crossover study Wallace et al. (2008) Uncontrolled prospective study
[43] [29]
[31]
F: Fentanyl; H: Hydromorphone; M: Morphine; O: Oxycodone.
dose limitation [12,13] unless adverse side effects would require a limitation. Compared with morphine, pharmacologic advantages of hydromorphone result in a reduced side-effect potential, making hydromorphone a particularly suitable choice for use in the abovementioned patient groups [14–17]. Hydromorphone is a dihydromorphine derivative, differing from morphine by substitution of the 6-hydroxy moiety with oxygen and hydro genation of the 7–8 double bond. These chemical modifications are responsible for the fact that the predominant metabolite of hydromorphone, hydromorphone-3-glucuronide, does not readily accumulate or cause adverse effects, unlike the metabolites of morphine [8]. Only some neuroexcitatory symptoms (agitation, myoclonus and seizures) are potentially of clinical relevance and may be due to hydromorphone-3-glucuronide [18]. A study of Wirz et al. demonstrated that the rate of nausea, emesis and constipation – well-known side effects of morphine – is significantly lower in treatment with hydromorphone than with morphine [11]. Morphine is metabolized to morphine3-glucuronide and morphine-6-glucuronide. The latter metabolite, which possesses analgesic activity, may accumulate in patients with renal insufficiency, possibly resulting in an increased
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incidence of side effects (e.g., sedation) and even intoxication (e.g., respiratory depression) [8]. The low plasma protein binding (8%) [8] make hydromorphone well suited, for example, for elderly and multimorbid patients [19]. In patients with renal impairment hydromorphone can be used with caution [17,20], although the recent EAPC guidelines recommend parenteral fentanyl or buprenorphine in these cases [5]. The elimination half-life of morphine-6-glucuronide is approximately 3 h in healthy individuals and up to 27 h in patients with renal insufficiency [21,22]. For the pain treatment of elderly patients buprenorphine is recommended in the consensus statement of Pergolizzi et al. [12]. However, different studies demonstrated reliable and welltolerated pain relief with hydromorphone [23–25]. Hydromorphone is CYP450 neutral – that is, it is not subject to N-demethylation via CYP3A4 [26], and its minimal interaction potential with other compounds is of no clinical relevance [27]. The bioavailability of orally administered hydromorphone is 10–65% [28]. In a randomized clinical trial, the safety and efficacy of hydromorphone as an analgesic alternative to morphine was demonstrated by Chang et al. [29]. Hydromorphone had a somewhat larger analgesic effect than morphine, which is consistent with the higher lipophilic
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characteristics of hydromorphone when compared with morphine [29]. Wallace et al. showed that the mean pain-relief level remained stable after conversion from morphine to extended-release hydromorphone and throughout treatment with this hydromorphone formulation [30]. The pharmacokinetic properties of hydromorphone have been investigated in several studies [28,29,31–33]. In a randomized, double-blind study, Hagen et al. studied the pharmacokinetics of hydromorphone and its major metabolite in cancer patients [27]. The advantages of hydromorphone in patients with hepatic and renal impairment, in palliative care patients [34,35] and in children, have been documented in several studies [17,36]. Indeed, a 2002 Cochrane review (updated in 2007) concluded that “hydromorphone is a potent analgesic for the management of acute and chronic pain. In terms of analgesic efficacy and tolerability, hydromorphone behaves like other strong opioids” [37]. In 2011, in a metaanalysis, Felden et al. found a small advantage of hydromorphone relative to morphine for analgesia but similar side effects [38]. They require further studies to verify a superiority of hydromorphone to morphine. But if there will be shown ‘only’ equivalence of hydromorphone and morphine, this confirms the recommendations of the EAPC guidelines 2012.
hydromorphone and controlled-release oxycodone with regard to pain relief and safety [41]. An immediate-release formulation is also available in capsule form (1.3- and 2.6-mg hydromorphone). Here, the onset of analgesia is within 30 min and the duration is 4 h. Equivalence in safety and efficacy was demonstrated for sustained-release and immediaterelease formulations of hydromorphone [42,43]. In addition to the capsule formulations for oral administration, formulations for parenteral injection (i.e., subcutaneous or intravenous) are available in vials of the following doses/volumes: 2 mg/1 ml, 10 mg/1 ml and 100 mg/10 ml. These concentrations allow low injection volumes at high dosages. The equianalgetic conversion factors of hydromorphone from one formulation to another are identical to those of morphine: from oral to intravenous 3:1 (oral dosage divided by 3), and from oral to subcutaneous 2:1 (oral dosage divided by 2) [44]. It is important to be careful with the individual dosage calculations, and the patients reactions should be monitored [10]. Subcutaneous and intravenous infusion of hydromorphone are comparable in pain relief and safety [33]. Although they are most commonly used subcutaneously or intravenously, good experience has been achieved with epidural or intrathecal application [45,46].
Preparations of hydromorphone
Flexibility
Hydromorphone is available in different formulations, for use in various clinical situations: sustained-release formulations, immediate-release formulations and injectable solutions. A number of different sustained-release formulations are available: capsules for twice-daily use, twice-daily tablets and once-daily tablets. There are some advantages of the capsules, for example, the possibility of opening the capsules and applicating the pellets via feeding tube [39]; they are also confirmed by the authors’ clinical experiences. Thus, a large proportion of the remainder of this short review article focuses on this formulation. Sustained-release capsules are available in hydromorphone concentrations of 4, 8, 16 and 24 mg. The onset of analgesia is within 2 h and the duration of analgesic effect is 12 h. In a randomized controlled trial for sustainedrelease hydromorphone, Hanna et al. demonstrated a better control of cancer pain than for morphine [40], and there are, for example, no significant differences between sustained-release
With the availability of different formulations of one particular opioid, the physician has the flexibility to adapt the route of administration to the individual patient situation. According to WHO recommendations, basic treatment of chronic pain should consist of oral administration ‘by the clock’; in the case of hydromorphone, sustainedrelease capsules should be given twice daily. Acute pain events (e.g., breakthrough pain) can be treated, or even prevented, with hydromorphone immediate-release capsules [47,48]. An important advantage of the capsules is the possibility to maintain enteral administration in patients with dysphagia [49]. Hydromorphone capsules, both the sustained-release and the immediate-release formulation, contain the opioid in pellets. The capsules can be opened to disperse the pellets on soft food or for application via a feeding tube [39,49]. The release principle is incorporated within the pellets and the analgesic mechanism remains unchanged by this administration procedure [39]. The formulation for parenteral injection is suitable for subcutaneous injection, or continuous
Pain Manage. (2013) 3(5)
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Hydromorphone in cancer pain & palliative care subcutaneous [50] or intravenous infusion [51,52]. Small injection volumes are particularly important when opioids are delivered subcutaneously [53]. Furthermore, intrathecal hydro morphone has been used in intractable nonmalignant pain, with the advantage of low injection volumes [54]. In addition, several studies provide good experience with hydromorphone as the opioid of choice in patient-controlled subcutaneous analgesia [55,56], as well as patient-controlled intravenous analgesia [57]. With hydromorphone, a complete set of formulations of one opioid is on hand, enabling flexible management of severe pain. Conclusion & future perspective Immediate-release and sustained-release hydromorphone, together with injectables for parenteral administration, represent a well-tolerated and effective set of formulations, ideally suited to cope with most pain situations related to severe cancer pain, analgesia in elderly/multimorbid patients and in palliative care. Hydromorphone is well tolerated in the patient groups described above. Pain can be successfully managed in a very flexible, fast and well-tolerated way. The same compound can be used both as a basic and an References Papers of special note have been highlighted as: of interest of considerable interest n n
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additional treatment – that is, to reduce acute pain. Having one opioid on hand, available in different dosages and formulations, may reduce the need to change opioid (i.e., in later stages of a progressing disease). Although morphine is the gold standard step III strong opioid in current WHO recommendations, it is anticipated that revisions to future treatment guidelines from WHO will acknowledge advances in the development of a range of formulations of other strong opioids, like hydromorphone and oxycodone, for the treatment of severe cancer pain and severe pain in palliative care. The EAPC guidelines have already taken into account and recommend morphine, hydromorphone and oxycodone as equivalent to morphine. Financial & competing interests disclosure KE Clemens has received lecture fees and research grants from Mundipharma. R Likar has received lecture fees from Mundipharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Medizin & Markt provided medical writing assistance, which was paid for by Mundipharma.
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Versatility of different pharmaceutical formulations of hydromorphone in the management of severe cancer pain and pain in palliative care
Practice Points
Katri E Clemens*1 & Rudolf Likar2 Opioids are the treatment of choice in severe chronic cancer pain and severe pain in palliative care, in
elderly patients and patients with multimorbidity. Until recently morphine was the gold standard for the treatment of severe cancer pain and nonmalignant
pain according to current WHO guidelines (step III). Several opioids, including hydromorphone, provide a suitable alternative treatment option. Now, morphine, hydromorphone and oxycodone are regarded as equivalent in the 2012 evidence-based recommondations from the European Association for Palliative Care. Hydromorphone is available in several formulations: sustained-release formulations (capsules for
twice-daily use, twice-daily tablets and once-daily tablets), immediate-release formulations (capsules) and injectable solutions (for intravenous, subcutaneous, intrathecal or epidural application). The versatility of different hydromorphone formulations provides the physician with the opportunity and
flexibility to adapt the route of administration to the individual patient’s situation. The availability of hydromorphone as sustained-release, immediate-release and parenteral formulations
renders this strong opioid particularly suitable for consistent opioid administration with predictable substance release. This may reduce the need to change opioids.
SUMMARY The management of severe pain situations requires therapeutic expertise in dealing with changes in pain intensity, analgesic limitations and individual patient needs. Opioids are the treatment of choice in severe pain. The availability of a broad range of opioids and formulations refined the options for improved pain treatment with a specific substance. These may include oral formulations, injectables and other applications suitable for different patient needs. Moreover, variable drug concentrations are most useful in clinical practice. This article briefly reviews the versatility of different hydromorphone formulations in the management of severe pain in palliative care and cancer. Limiting strong opioid treatment with one opioid substance in different formulations (adjuvants if necessary), according to varying requirements of patients, would be eligible for achieving a well-tolerated and effective pain therapy. Its versatility renders hydromorphone suitable for consistent opioid administration with predictable substance release, and may thus contribute to reducing the need for opioid change. Clinic for Palliative Medicine, MediClin, Robert Janker Klinik, Villenstr, 4–8, D-53129 Bonn, Germany Klinikum-Klagenfurt am Wörthersee, Department of Anesthesia, Feschnigstr 11, A-9020 Klagenfurt am Wörthersee, Austria *Author for correspondence: Tel.: +49 228 5306 301; [email protected] 1 2
10.2217/PMT.13.26 © 2013 Future Medicine Ltd
Pain Manage. (2013) 3(5), 369–375
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ISSN 1758-1869
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Review Clemens & Likar One of the most important medical goals in caring for elderly, multimorbid and incurable patients is to alleviate pain and, thus, optimize quality of life. It is only a minority of pain patients whose pain cannot be adequately alleviated, for example, by reason of intolerable side effects or development of antinociceptive tolerance – that is, most pain situations can be controlled by appropriate analgesic measures. From the medical perspective, the aging patient is characterized by considerable changes in physiology, for example, reduced renal function, reduced muscle mass, increased adipose tissue, but also a deterioration in cognitive abilities. Any pharmaceutical approach to the treatment of a particular disease has to consider these possible changes and their respective impact on elimination, plasma levels, drug interactions and impaired compliance [1]. Approximately 20–50% of patients with early-stage cancer, and 50–95% of patients with a progressive stage of cancer, experience pain [2,3]. According to WHO recommendations, strong opioids are the medication of choice for severe cancer pain [4]. A precondition for an effective therapy is the right choice of compound, the dose, time intervals and route of administration. Besides morphine, still referred to as the first-choice opioid in the WHO recommendations, hydromorphone was mentioned, until recently, only as a possible alternative, as well as other strong opioids like methadone, oxycodone or buprenorphine. Meanwhile, the WHO treatment guidelines are due to be updated, to incorporate progress that has been made in clinical experience with different formulations of opioids in the treatment of non malignant and cancer pain, and questioning whether morphine should still be referred to as the ‘gold standard’ [101,102]. The 2012 European Association for Palliative Care (EAPC) guidelines now recommend hydromorphone and oxycodone as equivalent to morphine as the firstchoice step III opioid for moderate-to-severe cancer pain, and methadone as a consideration of alternative [5,6]. This article provides an overview of available data relating to the versatility and resulting clinical benefit of pharmaceutical formulations of hydromorphone (WHO step III opioid) for the management of cancer pain and the treatment of pain of other etiology in palliative care, in elderly patients and patients with multimorbidity.
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Methods The authors searched databases and handsearched relevant journals to identify randomized and nonrandomized controlled trials assessing the analgesic effect of hydromorphone for cancer pain. The authors continuously searched, read and selected current literature (search terms were opioids, hydromorphone, cancer pain and palliative care) concerning pain management in cancer patients and palliative care patients, mainly using PubMed, MEDLINE, Cochrane Central Register of Controlled Trials Databases and other standard electronic literature databases from 1980 up to December 2011. Due to the special relevance in this patient group, information gathering focused on strong opioids. Only original clinical studies comparing hydromorphone (oral and parenteral applications) with other strong opioids or evaluating the efficacy and safety of a hydromorphone formulation were selected. Reviews and meta-analyses were excluded. Results Out of the initial 216 papers generated using the above mentioned search terms, the authors selected 15 original clinical studies for a closer analysis: seven randomized controlled trials, two randomized crossover studies, three uncontrolled retrospective studies, one uncontrolled prospective study, one nonrandomized prospective study and one clinical study. Authors, basic data and the design parameters are reported in Table 1. Hydromorphone
Hydromorphone, a semi-synthetic opioid, has opioid-agonistic properties [7]. The generally accepted conversion ratio of orally administered hydromorphone to morphine is a factor of 7.5 [8,9]. However, a variability in equianalgesic tables has been published. The bases of these tables, such as study design and population, are often not specified and they do not verify if equivalences were determined by single dose or at steady state. Furthermore there are interindividual differences in equivalents [10]. Taking the conversion ratio of the original tables into account, the analgesic efficacy of hydromorphone and morphine are comparable [9]. Wirz et al. found morphine with a higher rate of side effects (nausea, emesis and constipation) than hydromorphone [11]. Hydromorphone has no ceiling effect; it can be uptitrated according to the pain level without
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Hydromorphone in cancer pain & palliative care
Review
Table 1. The basic data and design parameters of the analyzed studies. Study (year)
Study design
Patients Administration route/formulation and compared (n) opioids
Ref.
Babul et al. (1995) Bruera et al. (1996) Chang et al. (2006) Clemens and Klaschik (2007) Clemens and Klaschik (2007) Hagen and Babul (1997) Hanna et al. (2008) Hays et al. (1994) Lee et al. (2001) Moriarty et al. (1999) Moulin et al. (1991) Thwaites et al. (2004) Vallner et al. (1981) Vashi et al. (2005)
Clinical study Randomized controlled trial Randomized controlled trial Retrospective study
2 95 198 81
Oral controlled-release H Oral H: extended-release vs immediate-release Intravenous H vs intravenous M Oral H vs transdermal F
[36]
[34]
Nonrandomized prospective study
11
Oral H and M
[35]
Randomized controlled trial
44
Oral H vs oral O
[41]
Randomized controlled trial Randomized controlled trial Uncontrolled retrospective study Randomized controlled trial Randomized controlled trial Uncontrolled retrospective study
200 48 55 100 20 48
[40] Oral H vs oral M [42] Oral H: extended-release vs immediate-release [17] Oral extended-release H [9] Oral H vs oral M Continuous parenteral H (intravenous/subcutaneous) [33] Continuous parenteral H (intravenous/subcutaneous) [18]
6 24, 26, 26 148
Intravenous H vs oral H Oral extended-release H
[32]
Oral extended-release H
[30]
Randomized two-way crossover pilot study Two single-dose, randomized crossover studies and one multiple-dose, two-way crossover study Wallace et al. (2008) Uncontrolled prospective study
[43] [29]
[31]
F: Fentanyl; H: Hydromorphone; M: Morphine; O: Oxycodone.
dose limitation [12,13] unless adverse side effects would require a limitation. Compared with morphine, pharmacologic advantages of hydromorphone result in a reduced side-effect potential, making hydromorphone a particularly suitable choice for use in the abovementioned patient groups [14–17]. Hydromorphone is a dihydromorphine derivative, differing from morphine by substitution of the 6-hydroxy moiety with oxygen and hydro genation of the 7–8 double bond. These chemical modifications are responsible for the fact that the predominant metabolite of hydromorphone, hydromorphone-3-glucuronide, does not readily accumulate or cause adverse effects, unlike the metabolites of morphine [8]. Only some neuroexcitatory symptoms (agitation, myoclonus and seizures) are potentially of clinical relevance and may be due to hydromorphone-3-glucuronide [18]. A study of Wirz et al. demonstrated that the rate of nausea, emesis and constipation – well-known side effects of morphine – is significantly lower in treatment with hydromorphone than with morphine [11]. Morphine is metabolized to morphine3-glucuronide and morphine-6-glucuronide. The latter metabolite, which possesses analgesic activity, may accumulate in patients with renal insufficiency, possibly resulting in an increased
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incidence of side effects (e.g., sedation) and even intoxication (e.g., respiratory depression) [8]. The low plasma protein binding (8%) [8] make hydromorphone well suited, for example, for elderly and multimorbid patients [19]. In patients with renal impairment hydromorphone can be used with caution [17,20], although the recent EAPC guidelines recommend parenteral fentanyl or buprenorphine in these cases [5]. The elimination half-life of morphine-6-glucuronide is approximately 3 h in healthy individuals and up to 27 h in patients with renal insufficiency [21,22]. For the pain treatment of elderly patients buprenorphine is recommended in the consensus statement of Pergolizzi et al. [12]. However, different studies demonstrated reliable and welltolerated pain relief with hydromorphone [23–25]. Hydromorphone is CYP450 neutral – that is, it is not subject to N-demethylation via CYP3A4 [26], and its minimal interaction potential with other compounds is of no clinical relevance [27]. The bioavailability of orally administered hydromorphone is 10–65% [28]. In a randomized clinical trial, the safety and efficacy of hydromorphone as an analgesic alternative to morphine was demonstrated by Chang et al. [29]. Hydromorphone had a somewhat larger analgesic effect than morphine, which is consistent with the higher lipophilic
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characteristics of hydromorphone when compared with morphine [29]. Wallace et al. showed that the mean pain-relief level remained stable after conversion from morphine to extended-release hydromorphone and throughout treatment with this hydromorphone formulation [30]. The pharmacokinetic properties of hydromorphone have been investigated in several studies [28,29,31–33]. In a randomized, double-blind study, Hagen et al. studied the pharmacokinetics of hydromorphone and its major metabolite in cancer patients [27]. The advantages of hydromorphone in patients with hepatic and renal impairment, in palliative care patients [34,35] and in children, have been documented in several studies [17,36]. Indeed, a 2002 Cochrane review (updated in 2007) concluded that “hydromorphone is a potent analgesic for the management of acute and chronic pain. In terms of analgesic efficacy and tolerability, hydromorphone behaves like other strong opioids” [37]. In 2011, in a metaanalysis, Felden et al. found a small advantage of hydromorphone relative to morphine for analgesia but similar side effects [38]. They require further studies to verify a superiority of hydromorphone to morphine. But if there will be shown ‘only’ equivalence of hydromorphone and morphine, this confirms the recommendations of the EAPC guidelines 2012.
hydromorphone and controlled-release oxycodone with regard to pain relief and safety [41]. An immediate-release formulation is also available in capsule form (1.3- and 2.6-mg hydromorphone). Here, the onset of analgesia is within 30 min and the duration is 4 h. Equivalence in safety and efficacy was demonstrated for sustained-release and immediaterelease formulations of hydromorphone [42,43]. In addition to the capsule formulations for oral administration, formulations for parenteral injection (i.e., subcutaneous or intravenous) are available in vials of the following doses/volumes: 2 mg/1 ml, 10 mg/1 ml and 100 mg/10 ml. These concentrations allow low injection volumes at high dosages. The equianalgetic conversion factors of hydromorphone from one formulation to another are identical to those of morphine: from oral to intravenous 3:1 (oral dosage divided by 3), and from oral to subcutaneous 2:1 (oral dosage divided by 2) [44]. It is important to be careful with the individual dosage calculations, and the patients reactions should be monitored [10]. Subcutaneous and intravenous infusion of hydromorphone are comparable in pain relief and safety [33]. Although they are most commonly used subcutaneously or intravenously, good experience has been achieved with epidural or intrathecal application [45,46].
Preparations of hydromorphone
Flexibility
Hydromorphone is available in different formulations, for use in various clinical situations: sustained-release formulations, immediate-release formulations and injectable solutions. A number of different sustained-release formulations are available: capsules for twice-daily use, twice-daily tablets and once-daily tablets. There are some advantages of the capsules, for example, the possibility of opening the capsules and applicating the pellets via feeding tube [39]; they are also confirmed by the authors’ clinical experiences. Thus, a large proportion of the remainder of this short review article focuses on this formulation. Sustained-release capsules are available in hydromorphone concentrations of 4, 8, 16 and 24 mg. The onset of analgesia is within 2 h and the duration of analgesic effect is 12 h. In a randomized controlled trial for sustainedrelease hydromorphone, Hanna et al. demonstrated a better control of cancer pain than for morphine [40], and there are, for example, no significant differences between sustained-release
With the availability of different formulations of one particular opioid, the physician has the flexibility to adapt the route of administration to the individual patient situation. According to WHO recommendations, basic treatment of chronic pain should consist of oral administration ‘by the clock’; in the case of hydromorphone, sustainedrelease capsules should be given twice daily. Acute pain events (e.g., breakthrough pain) can be treated, or even prevented, with hydromorphone immediate-release capsules [47,48]. An important advantage of the capsules is the possibility to maintain enteral administration in patients with dysphagia [49]. Hydromorphone capsules, both the sustained-release and the immediate-release formulation, contain the opioid in pellets. The capsules can be opened to disperse the pellets on soft food or for application via a feeding tube [39,49]. The release principle is incorporated within the pellets and the analgesic mechanism remains unchanged by this administration procedure [39]. The formulation for parenteral injection is suitable for subcutaneous injection, or continuous
Pain Manage. (2013) 3(5)
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Hydromorphone in cancer pain & palliative care subcutaneous [50] or intravenous infusion [51,52]. Small injection volumes are particularly important when opioids are delivered subcutaneously [53]. Furthermore, intrathecal hydro morphone has been used in intractable nonmalignant pain, with the advantage of low injection volumes [54]. In addition, several studies provide good experience with hydromorphone as the opioid of choice in patient-controlled subcutaneous analgesia [55,56], as well as patient-controlled intravenous analgesia [57]. With hydromorphone, a complete set of formulations of one opioid is on hand, enabling flexible management of severe pain. Conclusion & future perspective Immediate-release and sustained-release hydromorphone, together with injectables for parenteral administration, represent a well-tolerated and effective set of formulations, ideally suited to cope with most pain situations related to severe cancer pain, analgesia in elderly/multimorbid patients and in palliative care. Hydromorphone is well tolerated in the patient groups described above. Pain can be successfully managed in a very flexible, fast and well-tolerated way. The same compound can be used both as a basic and an References Papers of special note have been highlighted as: of interest of considerable interest n n
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