This Invited Commentary accompanies the following article:
Lee YS, Park YC, Kim JH, et al. Intrathecal hydromorphone added to hyperbaric bupivacaine for postoperative pain relief after knee arthroscopic surgery: a prospective, randomised, controlled trial. Eur J Anaesthesiol 2012; 29:17–21.
Unlicensed use of a drug describes a deviation from the labelled indication, dosage, dose regimen or patient population.1 In a prospective, randomised, controlled trial, Lee et al.2 sought to determine the optimal dose of intrathecal hydromorphone to provide effective and prolonged postoperative pain relief after arthroscopic knee surgery. Clearly in this context, the use of hydromorphone, a potent μ-opioid agonist, falls in the unlicensed use category: the solution is not licensed for spinal use, intrathecal administration has not undergone full neurotoxicity screening and intrathecal use is rare and to date has been used only in the management of intractable chronic pain.3
Unlicensed use of drugs is prevalent in medical practice and involves 21% of all prescriptions (up to 83% for some diseases). Records of the use of most unlicensed drugs (73%, 95% confidence interval 61–84%) show little evidence of clinical efficacy and have little or no scientific support.4 In the practice of anaesthesiology and pain medicine, new routes and modes of administration as well as variations in dose and applications for medications are often required to solve complex problems. Unlicensed use of some drugs can be important for medical care and development of new treatments. In the study from Lee et al.,2 the purpose of the authors was to investigate the use of intrathecal hydromorphone instead of intrathecal morphine to obtain a similar analgesic effect but with less side-effects such as pruritus and nausea. However, the unlicensed use of a drug involving its administration in the vicinity of nerves (perineural route), and particularly the neuraxial route (i.e. epidural, caudal, intrathecal), brings additional concerns.1 The choice made for neuraxial analgesics should always result from a balance between the risks (neurotoxicity and side-effects) and the benefits (pain relief) expected in either the short term or longer term.
Pain experienced after operative knee arthroscopic procedures such as meniscectomy or repair of the anterior cruciate ligament ranges from moderate to severe, is maximal during the first 8 h postoperatively and may persist longer, making discharge difficult for some patients whose surgery was intended to be in the ambulatory setting.5 In addition, optimal postoperative pain management plays an important role in surgical outcome. Minimally invasive procedures such as knee arthroscopy may lead to chronic postsurgical pain, recognised as a significant healthcare problem, in 11–21% of patients.6 Risk factors for persistent disability after knee arthroscopy include moderate-to-severe acute pain, age greater than 50 years and female sex. To produce effective and prolonged analgesia allowing comfort and early mobilisation, several drugs and combinations have been tested, mostly by direct injection into the joint. These techniques have shown inconsistent analgesic efficacy and a finite risk of chondrotoxicity. Among analgesic alternatives, the intrathecal administration of a low dose of morphine has also been assessed because of its recognised long-lasting effect.7,8
Considering the balance between risks and benefits for patients, the study by Lee et al.2 raises two major questions. First, what is the place for a long-lasting intrathecal opioid in minimally invasive surgery and particularly in an ambulatory setting? Second, is it acceptable to use an unlicensed drug intrathecally with very limited neurotoxicity screening?
According to meta-analysis, a single dose of intrathecal morphine decreases the 24-h pain intensity by about 1 cm on a 10-cm visual analogue scale after major surgery.9 The same effect could be observed after the systemic administration of a NSAID. Although one patient in five has a contraindication to receiving a NSAID, it is necessary to question the rationale of administration of intrathecal morphine to treat pain after minor procedures. Spinal morphine in the postoperative setting carries many inconvenient side-effects such as pruritus, nausea and vomiting, and urinary retention, as well as the rare but most feared potential risk of delayed respiratory depression.9 Will intrathecal hydromorphone prove to be better than morphine? The trial from Lee et al.2 does not provide an answer because they did not compare the two drugs.
There are currently very few studies which have made a direct comparison between morphine and hydromorphone which makes the estimation of equianalgesic doses uncertain.3 Although hydromorphone was introduced into clinical practice many years ago (1926), the meta-analysis by Quigley10 does not support its superiority over morphine for the management of moderate-to-severe pain in terms of analgesic efficacy and tolerability. According to the results from Lee et al.,2 who administered low doses of hydromorphone, assuming a potential equipotency with spinal morphine of 1 : 7–10, the duration of postoperative analgesia and the incidence of common side-effects does not really differ from those already reported by others after intrathecal administration of morphine 50–160 μg for similar arthroscopic procedures (Table 1).2,7,8
The second concern is the use of intrathecal hydromorphone beyond a chronic pain context. Data available about spinal hydromorphone in acute pain conditions are scarce and current reports refer exclusively to its epidural administration which seems to provide effective analgesia and to be associated with a reasonable profile of adverse effects.11 Like morphine,12 the duration and efficacy of hydromorphone analgesia are probably greater after administration by the epidural than the intrathecal route. The duration of action after a single epidural dose of hydromorphone varies from 8 to 19 h.3 However, it is worth noting that a dosage regimen for epidural administration may not be suitable for intrathecal administration because of the risk of local tissue toxicity. Conversely, a drug which is approved for intrathecal use may not be appropriate for epidural use because of risks of systemic toxicity. Moreover, the use of preservative-free preparations is not a guarantee of the absence of neurotoxicity. Although the intrathecal doses used in the present study are very low and probably well tolerated, hydromorphone has not undergone full neurotoxicity screening and preclinical toxicology testing has been undertaken in only one animal species (sheep) to mimic infusion in chronic pain conditions (large doses and prolonged administration) to assess the potential development of inflammatory granulomata.13
In conclusion, the clinical trial of Lee et al.2 reinforces previous findings which have failed to demonstrate any superiority of hydromorphone over morphine in terms of either analgesia or side-effects. The unlicensed use of intrathecal hydromorphone forces us to reconsider even more seriously the balance between risks and benefits for the patient (‘Primum, non nocere’, Hippocrates). Last but not least, we should note that hydromorphone is almost 30 times more expensive than morphine on the European market.
The authors did not benefit from any financial support and have no conflicts of interest to disclose.
This article was checked by the editors but was not sent for peer review.
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Intrathecal hydromorphone added to hyperbaric bupivacaine for postoperative pain relief after knee arthroscopic surgery: a prospective, randomised, controlled trial. Eur J Anaesthesiol
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