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Strong opioids for noncancer pain due to musculoskeletal diseases: Not more effective than acetaminophen or NSAIDs
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Review
Strong opioids for noncancer pain due to musculoskeletal diseases: Not more effective than acetaminophen or NSAIDs Jean-Marie Berthelot ∗ , Christelle Darrieutort-Lafitte , Benoit Le Goff , Yves Maugars Service de rhumatologie, Hôtel-Dieu, CHU de Nantes, place Alexis-Ricordeau, 44093 Nantes cedex 01, France
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Article history: Accepted 3 March 2015 Available online xxx Keywords: Opioids Morphine Morphine derivatives Pain Osteoarthritis Low back pain Efficacy Placebo Acetaminophen Paracetamol Nonsteroidal anti-inflammatory drugs
a b s t r a c t The classification of morphine as a step III analgesic, based on pharmacological data, creates a strong bias toward a belief in the efficacy of this drug. However, double-blind emergency-room trials showed similar levels of pain relief with intravenous acetaminophen as with intravenous morphine in patients with renal colic, low back pain or acute limb pain. In patients with chronic noncancer low back pain, morphine and other strong opioids in dosages of up to 100 mg/day were only slightly more effective than their placebos, no more effective than acetaminophen, and somewhat less effective than nonsteroidal anti-inflammatory drugs (NSAIDs). In patients with osteoarthritis, strong opioids were not more effective than NSAIDs and, in some studies, than placebos. The only randomized controlled trial in patients with sciatica found no difference with the placebo. Chronic use of strong opioids can induce hyperalgesia in some patients. Hyperpathia with increased sensitivity to cold leading the patient to request higher dosages should suggest opioid-induced hyperalgesia. Pain specialists in the US have issued a petition asking that strong opioids be used in dosages no higher than 100 mg/day of morphine-equivalent, in an effort to decrease the high rate of mortality due to the misuse and abuse of strong opioids (10,000 deaths/year in the US). Healthcare providers often overestimate the efficacy of step III analgesics, despite pain score decreases of only 0.8 to 1.2 points. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. The designation “strong” opioids is misleading Several factors explain the common perception that morphine is necessarily effective in relieving pain. First, morphine is placed at the top of the WHO analgesic ladder (on step III), based chiefly on pharmacological evidence, namely, affinity for the mu receptors. This fact, combined with the restricted-access status of morphine, confers on this drug a forbidden-fruit appeal that strengthens its placebo effect. Second, we all fear severe pain and are therefore unwilling to believe that morphine would fail to provide relief. Third, charges by several healthcare authorities that pain is inadequately treated have induced guilt among healthcare providers [1]. The ensuing recommendations suggested implicitly that drugs characterized by far greater efficacy were available (i.e., “strong” opioids) and insufficiently used. This fallacious argument has placed opioids on a pedestal, and most patients and healthcare providers (including nurses) believe that standard morphine dosages are necessarily far more effective than acetaminophen and,
of course, than placebos. The legitimacy of this belief, particularly regarding patients with noncancer pain, deserves discussion. 2. Morphine (except in very high dosages) is not more effective on average than acetaminophen, and sometimes even than placebos, in patients with noncancer pain The scarcity of high-quality studies (randomized, doubleblinded, and controlled versus a placebo or another analgesic such as acetaminophen) on the efficacy of step III analgesics is stunning, given the long history of widespread use and abuse of these drugs. For instance, in patients with sciatica, a single randomized trial has compared morphine to a placebo. Furthermore, in this trial, the difference in efficacy between morphine (10 to 90 mg/day; mean dosage, 62 ± 29 mg/day) and the placebo was only 7% [2]. Although the number of patients was small, this near-equivalence between morphine and the placebo probably discouraged further trials. 2.1. Acute noncancer pain
∗ Corresponding author. E-mail address: [email protected] (J.-M. Berthelot).
The above-mentioned trial [2] was done in patients with chronic sciatic pain. However, in several randomized doubleblind trials, intravenous (IV) morphine was not more effective
http://dx.doi.org/10.1016/j.jbspin.2015.08.003 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
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than IV acetaminophen in relieving acute pain in emergencyroom patients. Thus, in 146 patients with renal colic treated by IV infusion, 1 g of acetaminophen was as effective as 0.1 mg/kg of morphine: the pain score decreases after 30 minutes were 43 and 40 mm, respectively (versus 27 mm with the placebo) [3]. IV paracetamol was more effective than IV morphine in a randomized trial of 73 patients with renal colic (64-mm versus 57-mm pain score decreases, respectively) [4]. Acetaminophen and morphine administered via patient-controlled analgesia for post-laparotomy pain showed little difference in efficacy, with a small early advantage of morphine that was no longer present after 4 hours [5]. Similar equivalence between IV acetaminophen and IV morphine in standard dosages has been reported in patients with musculoskeletal diseases. In 137 patients with acute low back pain, IV morphine (0.1 mg/kg) was not more effective than IV acetaminophen (1 g): the pain score decreases after 30 minutes were 67 mm and 65 mm, respectively [6]. In 55 patients with extremely intense acute limb pain (score > 7/10), pain relief was not different between 1 g of IV acetaminophen and 10 mg of IV morphine [7]. Similarly, morphine was only minimally effective in post-cholecystectomy patients, inducing a mean pain score decrease of only 0.5/10 between 9 and 12 hours after the procedure [8]. After knee or hip arthroplasty, morphine 60 mg/day was not better than a placebo in alleviating the pain or allowing rehabilitation initiation and was associated with significantly higher rates of vomiting and subsequent drug dependency (P < 0.0001) [9]. Considerably higher morphine dosages might produce greater pain relief compared to acetaminophen. However, no reviews assessing this possibility are available. As with chronic pain, most studies in acute pain used morphine-equivalent dosages that were substantial but did not exceed 90 mg/day [10]. The evidence collected on morphine can probably be extrapolated to the other step III analgesics and, with even greater reason, to other routes of administration than intravenous infusion, despite the absence of randomized trials. 2.2. Chronic noncancer pain Chronic pain has been the focus of a far larger number of trials, which have been assessed in Cochrane meta-analyses. A review of 31 studies of neuropathic pain provided some evidence that opioids might be slightly more effective than placebos, with a pain score decrease by at least one-third in 57% of patients taking morphine versus 34% of those taking a placebo [11]. The authors cautioned that the difference in efficacy should be viewed with circumspection, as several sources of bias were identified and no trial of strong opioids versus acetaminophen was available [11]. Another meta-analysis found no proof of efficacy of oxycodone (Oxycontin® , Oxynorm® ) used to treat diabetic neuropathy, postherpetic neuralgia, or fibromyalgia [12]. In contrast, adverse events were common. A Cochrane review included 15 studies of low back pain, of which only 6 evaluated strong opioids [13]. The results suggested small benefits of opioid therapy compared to a placebo in the short-term, with a greater effect on pain than on function, but no evidence of long-term efficacy. For instance, in a randomized double-blind trial comparing hydromorphone (Sophidone® ) to a placebo in patients with good opioid response and safety profiles, the difference in efficacy after 3 months was only 1.4/10 points, and the proportion of patients improved by at least 30% was only 61% with hydromorphone versus 43% with the placebo [14]. This effect of hydromorphone was similar to that of acetaminophen (which was not more effective than a placebo in a study of acute low back pain [15]). These data explain that the level of evidence supporting the efficacy of strong opioids (including morphine, hydromorphone [Sophidone® ], oxycodone [Oxycontin® , Oxynorm® ] and oxymorphone) in 1887 patients was characterized as only moderate in a Cochrane review [13]. Similarly, a systematic review of NSAIDs
and opioids in patients with chronic low back pain showed only modest effects of both drug classes, with greater efficacy of NSAIDs compared to opioids [16]. A recent systematic review of analgesic effects in osteoarthritis showed that opioids were not more effective than NSAIDs or duloxetine (Cimbalta® ) [16]. Oxycodone (Oxycontin® , Oxynorm® ) and hydromorphone (Sophidone® ) may be even less effective and not superior over a placebo [17]. Anesthesiologists in the US recently suggested a revision of current guidelines to explicitly indicate that the expected pain score decrease after 3 months of strong opioid therapy for noncancer pain was similar to that seen with NSAIDs and only about 0.8 to 1.2/10 points [18]. In patients with an inadequate response or escape phenomenon, a dosage increase is often the preferred option, as opposed to IV administration or switching to another opioid. When treating noncancer pain due to musculoskeletal disease, it remains unclear whether increasing the dosage to the levels used in cancer can provide a clinically meaningful improvement (usually defined as an at least 1.5-point pain score decrease), despite the long-term toxicity of step III analgesics. A randomized placebo-controlled trial of 103 patients with chronic low back pain assessed sustained-release morphine in titrated dosages of up to a mean of 78 mg/day (sufficient sedation or development of adverse events) [19] Although a mean pain score improvement of 44% was obtained, a 42% decrease in analgesic efficacy was noted after 1 month. Also in patients with chronic low back pain, the difference in efficacy between sustainedrelease oxycodone (Oxycontin® , Oxynorm® ) and a placebo was only 0.7/10 points (mean pain score decrease on a 100-mm scale, 55.9 ± 25.4 mm with oxycodone versus 48.6 ± 23.1 mm with a placebo), although the oxycodone dosage could be titrated up to 40 mg every 12 hours [20]. In the US, the current pressure to relieve pain by any means has led to an epidemic of high-dose opioid use in patients with noncancer pain [21]. Recent work has established that the vast majority of patients on high-dose strong opioids fail to experience significant decreases in pain intensity or remain very dissatisfied with the treatment, in particular due to the development of hyperalgesia and drug tolerance (which decrease the efficacy of strong opioids) [22]. Similar trends have been documented in Europe. In a recent study from Norway, 14,477 of 46,000 individuals reported chronic noncancer pain and, among them, 15% took opioids including 3% who took high-dose step III opioids continuously [23]. In this last subgroup, three-quarters of patients reported persistent severe or very severe pain. These data support the results of the meta-analyses indicating that efficacy is disappointingly low. 3. The efficacy of opioids may be greater against cancer pain, due to the use of higher dosages, but also declines over time Some cancer patients experience good outcomes. Thus, 50 to 65% survive for longer than 2 years or achieve a full recovery, and there are at least 12 million cancer survivors in the US [24]. However, most randomized trials of opioids involved short-term treatment, usually for 4 weeks. Consequently, their results lead to overestimation of long-term efficacy (since efficacy diminishes over time due to opioid-induced hyperalgesia and to drug tolerance) and to underestimation of toxicity [25]. 3.1. Initial efficacy of high-dose opioids In cancer pain, morphine is used in higher dosages of 25 to 2000 mg per day, with a mean of 100–250 mg/day (i.e., 2 to 4 times higher than in noncancer musculoskeletal diseases). Because physicians are biased to believe that morphine in these high doses is
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necessarily effective, no randomized placebo-controlled trials have been conducted in morphine-naive patients and very few have compared morphine to other analgesics [26,27]. The only randomized placebo-controlled trial was done in a small group of only 19 patients with a history of immediate-release morphine therapy [27]. The patients were switched to sustained-release morphine then to either a placebo or the previous dosage of immediaterelease morphine. At the end of the trial, the level of analgesia was not different between the group returned to immediate-release morphine and the group given the placebo [27]. The lack of placebocontrolled trials and the possibility of large improvements brought about by a placebo or Hawthorne effect or by anticancer treatments (radiotherapy and chemotherapy) preclude an evaluation of the potential contribution of opioids to the observed benefits [25,28,29]. In a randomized placebo-controlled trial of tramadol to treat cancer patients with presumably neuropathic pain, the pain score improvement after 1 month was 57% with tramadol (mean pain score decrease from 6.8 to 2.9) but was also 39% with the placebo (mean pain score decrease from 7.0 to 4.3) [30]. Nevertheless, a real short-term effect of high-dose opioid therapy seems highly likely, particularly with fentanyl (Durogesic® ). In breakthrough cancer pain, nasal transmucosal fentanyl was more effective than intermediate dosages of oral morphine [31]. Similarly, in chronic cancer pain, proof of efficacy seems stronger for fentanyl than for other opioids [24], although the magnitude of the effect is unclear. However, this slightly greater efficacy is obtained at the expense of faster dependency induction. As no placebo-controlled trials are available in patients with cancer pain, Cochrane reviews have focused on studies comparing several opioids. Design flaws are common, with the primary outcome measure in most cases being “satisfactory” analgesia [29]. A review of oral step III analgesic therapy including 62 trials in a total of 4241 patients showed that a mean pain score of about 3/10 was obtained in slightly less than one-third of the trials (18/62, 29%) [29]. A recent systematic review showed limited efficacy of opioids for relieving cancer pain, with substantial toxicity [32]. Furthermore, recent opioids such as oxycodone (Oxycontin® , Oxynorm® ) or hydromorphone (Sophidone® ) were not more effective than morphine [32]. Similarly, although several recommendations indicate that preference should be given to sustained-release forms, the six randomized trials that compared sustained-release to immediate-release opioids found no difference [33] in efficacy or adverse events, particularly addiction, both in noncancer pain and in cancer pain [34]. 3.2. The effectiveness of morphine declines over time Pain that recurs or increases despite continued opioid therapy may be due to cancer progression promoted by the immunosuppressive effect of high-dose opioids [35]. Published trials assessed only short-term outcomes and, consequently, missed this effect, as well as escape phenomenon, drug tolerance and, perhaps, opioid-induced hyperalgesia. These events can induce both an exacerbation of the pain and a need to increase the dosages, in some cases without consulting the physician. Urine drug testing in patients participating in clinical trials has been recommended to identify cases of abuse [36]. 4. Awareness of opioid-induced hyperalgesia is low among healthcare providers Patients with morphine tolerance, dependency, or hyperalgesia all report an increase in pain intensity and request higher dosages. However, the management strategy differs across these three situations. In patients with tolerance, the opioid gradually becomes
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less effective, and higher dosages are therefore required. Tolerance is difficult to differentiate from a disease flare in patients with rheumatic diseases. Switching among opioids has been suggested to decrease the impact of tolerance, but no meta-analyses have obtained convincing support for this strategy [37], which increases the risk of dependency by prolonging the opioid exposure. Dependency is a perceived need to increase the dosage, due to craving. The symptoms of dependency may be physical (shaking, sweating, tachycardia, hypertension, mydriasis, abdominal pain, muscle cramps, confusion, agitation, anxiety, depression) and/or psychological (withdrawal from usual centers of interest and social interactions, as the patient focuses on obtaining the drug). Dependency is the downside of the feelings of euphoria that can be generated by opioids, particularly when delivered intravenously or via other routes characterized by rapid absorption. When crushed or chewed, oxycodone (Oxycontin® , Oxynorm® ) may have an effect similar to that of heroin, and the same may be true of hydromorphone (Sophidone® ), with both drugs then becoming capable of inducing dependency after a single dose. The frequency of dependency varies according to the severity criteria used to define this condition. Only patients who seek medical advice because of dependency or regularly request dosage increases can be easily identified. The most pessimistic estimate was made by the National Center on Addiction and Substance Abuse at Columbia University in the US in 2005: among patients receiving opioid therapy for pain, 30% (15 million individuals) were believed to be dependent [38]. It is to be hoped that many of these patients had transient opioid abuse with episodes of physical dependency, as opposed to longterm psychological dependency. Support for this possibility comes from a study in patients with no history of substance abuse or opioid therapy who were started on oxycodone (Oxycontin® , Oxynorm® ): subsequent severe chronic dependency occurred in only 0.6% of cases (1 patient in 150) [39]. Nevertheless, in the US, this frequency translates into several tens of thousands of new cases of severe opioid dependency each year, and this is only a floor value. Far higher frequencies would no doubt be documented among patients with a history of addictive behaviors, who are more likely to use opioids as substitutes for other drugs and thus move easily from opioids to heroin [40]. Opioid-induced hyperalgesia is a paradoxical increase in pain intensity during long-term opioid therapy. This phenomenon is most common among drug abusers and in patients on high-dose opioids for long periods (generally more than 4 weeks). However, faster onset of opioid-induced hyperalgesia has been reported in patients with no history of drug abuse or opioid exposure [41]. A review of 27 randomized controlled trials of intraoperative analgesia comparing an opioid to a placebo showed that patients having unknowingly received high-dose opioids (chiefly remifentanil) during surgery reported worse postoperative pain than did patients given intraoperative placebo therapy (difference, 0.94/10 after 1 hour, 0.71/10 after 4 hours, and 0.3/10 after 24 hours), despite higher dosages of postoperative opioids [42]. Exposure to low-dose opioids may increase heat sensitivity [43] and, in experimental models, hyperesthesia can occur with very low dosages. This situation raises major diagnostic challenges with weaning symptoms and drug dependency. Opioid-induced hyperalgesia may develop in up to 25% of all patients on long-term opioid therapy [44]. Although this finding is probably applicable only to the use of dosages greater than 100 mg/d, opioid-induced hyperalgesia should be considered in patients with hyperpathia and allodynia, before the development of myoclonus or even seizures or delirium [40]. A diagnosis of opioid-induced hyperalgesia is particularly likely if the pain worsens after an increase in the opioid dosage. Switching among opioids (including methadone) or using NMDA receptor antagonists (dextromethorphan and ketamine) can diminish drug-induced hyperalgesia but may merely prolong
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the opioid exposure, thereby generating further drawbacks and risks. 5. Petition in the US to set ceiling morphine dosages and durations The “war against pain” launched two decades ago in the US has been described as similar to opening Pandora’s box, particularly by allowing nonanesthesiologists to administer potent anesthetics [45]. Clearly, this war has been lost by many patients: it is estimated to have caused 10,000 to 20,000 drug-overdose deaths in the US (and the many other adverse effects of long-term opioids also need to be considered [46,47]). This result is not surprising, since so-called “strong” opioids, although more toxic than hoped, induce limited benefits. The moderate relief they may provide after a marked dosage increase is often counterbalanced by secondary loss of effectiveness and, most importantly, by dependency, a rare but potentially devastating complication. The promise that complete pain relief was within reach set an unattainable target, thus probably inducing considerable frustration in the public, making most individuals less tolerant to pain, and increasing their tendency to catastrophize [48]. Anesthesiologists specialized in pain control have warned European countries to steer clear of the very bad example set by the US in this field [21], particularly when analgesic therapy is given without the detection and treatment of the cause of pain. Although acetaminophen [49] and NSAIDs also have limitations, a group of pain-control specialists and anesthesiologists in the US has issued a petition requesting restrictions to the use of step III analgesics in patients with noncancer pain, namely, not exceeding 100 mg of morphine-equivalent per day for no longer than 100 days [50]. 6. Conclusion The answer to the question asked at the beginning of this review is clear: the designation “strong” opioids is misleading if the word “strong” is intended to reflect analgesic potency. On the other hand, the toxicity of these drugs, which is severe in some cases (over 10,000 deaths per year in the US) [20] does warrant their classification as step III analgesics [51]. If other analgesics are truly ineffective, the use of “strong” opioids for short periods (<3 months) remains legitimate and even advisable, in particular because of the major placebo and Hawthorne effects that result from a strong belief in their efficacy [52]. Nevertheless, “strong” opioids have not consistently been proven more effective than acetaminophen or NSAIDs in relieving noncancer pain due to musculoskeletal diseases. Neither have “strong” opioids always been found superior over a placebo in a variety of conditions such as low back pain [53] or sciatica [2], despite widespread use [54]. Cannabis also has only moderate effects, with substantial toxicity as a major drawback [55]. The development of new analgesic classes or nonpharmacological approaches [56] is awaited impatiently by all rheumatologists, whose everyday practice involves striving to relieve patients from chronic pain. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Van Zee A. The promotion and marketing of OxyContin: commercial triumph, public health tragedy. Am J Public Health 2009;99:221–7. [2] Khoromi S, Cui L, Nackers L, et al. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain 2007;130:66–75.
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[43] Wang F, Stefano GB, Kream RM. Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: etiological contribution to complex regional pain syndromes (part II). Med Sci Monit 2014;20:1188–200. [44] Ackeman 3rd WE. Paroxysmal opioid-induced pain and hyperalgesia. J Ky Med Assoc 2006;104:419–23. [45] Delaunay L, Gentilij M, Cittanova ML, et al. Anaesthesia by nonanaesthesiologists: the Pandora Box is open! Eur J Anaesthesiol 2012;29:50–1. [46] Alexander GC, Kruszewski SP, Webster DW. Rethinking opioid prescribing to protect patient safety and public health. JAMA 2012;308:1865–6. [47] Schiltenwolf M, Akbar M, Hug A, et al. Evidence of specific cognitive deficits in patients with chronic low back pain under long-term substitution treatment of opioids. Pain Physician 2014;17:9–20. [48] Penhoat M, Saraux A, Le Goff B, et al. High pain catastrophizing scores in onefourth of patients on biotherapy for spondylarthritis or rheumatoid arthritis. Joint Bone Spine 2014;81:235–9. [49] Richette P. How safe is acetaminophen in rheumatology? Joint Bone Spine 2014;81:4–5. [50] Kuehn BM. Petition targets painkiller marketing in effort to curb overdose deaths. JAMA 2012;308:1194–6. [51] Bannwarth B. Irrelevance of the WHO analgesic ladder for managing rheumatic pain. Joint Bone Spine 2010;77:1–3. [52] Berthelot JM, Le Goff B, Maugars Y. The Hawthorne effect: stronger than the placebo effect? Joint Bone Spine 2011;78:335–6. [53] Bannwarth B, Kostine M, Shipley E. Nonspecific low back pain: assessment of available medications. Joint Bone Spine 2012;79:134–6. [54] Berthelot JM, Perrot L, Glémarec J, et al. Do we use morphine often enough? An opinion survey in 100 rheumatology department patients. Joint Bone Spine 2000;67:326–30. [55] Martin-Sanchez E, Furukawa TA, Taylor J, et al. Systematic review and metaanalysis of cannabis treatment for chronic pain. Pain Med 2009;10:1353–68. [56] Pérocheau D, Laroche F, Perrot S. Relieving pain in rheumatology patients: repetitive transcranial magnetic stimulation (rTMS), a developing approach. Joint Bone Spine 2014;81:22–6.
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Available online at
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Review
Strong opioids for noncancer pain due to musculoskeletal diseases: Not more effective than acetaminophen or NSAIDs Jean-Marie Berthelot ∗ , Christelle Darrieutort-Lafitte , Benoit Le Goff , Yves Maugars Service de rhumatologie, Hôtel-Dieu, CHU de Nantes, place Alexis-Ricordeau, 44093 Nantes cedex 01, France
a r t i c l e
i n f o
Article history: Accepted 3 March 2015 Available online xxx Keywords: Opioids Morphine Morphine derivatives Pain Osteoarthritis Low back pain Efficacy Placebo Acetaminophen Paracetamol Nonsteroidal anti-inflammatory drugs
a b s t r a c t The classification of morphine as a step III analgesic, based on pharmacological data, creates a strong bias toward a belief in the efficacy of this drug. However, double-blind emergency-room trials showed similar levels of pain relief with intravenous acetaminophen as with intravenous morphine in patients with renal colic, low back pain or acute limb pain. In patients with chronic noncancer low back pain, morphine and other strong opioids in dosages of up to 100 mg/day were only slightly more effective than their placebos, no more effective than acetaminophen, and somewhat less effective than nonsteroidal anti-inflammatory drugs (NSAIDs). In patients with osteoarthritis, strong opioids were not more effective than NSAIDs and, in some studies, than placebos. The only randomized controlled trial in patients with sciatica found no difference with the placebo. Chronic use of strong opioids can induce hyperalgesia in some patients. Hyperpathia with increased sensitivity to cold leading the patient to request higher dosages should suggest opioid-induced hyperalgesia. Pain specialists in the US have issued a petition asking that strong opioids be used in dosages no higher than 100 mg/day of morphine-equivalent, in an effort to decrease the high rate of mortality due to the misuse and abuse of strong opioids (10,000 deaths/year in the US). Healthcare providers often overestimate the efficacy of step III analgesics, despite pain score decreases of only 0.8 to 1.2 points. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. The designation “strong” opioids is misleading Several factors explain the common perception that morphine is necessarily effective in relieving pain. First, morphine is placed at the top of the WHO analgesic ladder (on step III), based chiefly on pharmacological evidence, namely, affinity for the mu receptors. This fact, combined with the restricted-access status of morphine, confers on this drug a forbidden-fruit appeal that strengthens its placebo effect. Second, we all fear severe pain and are therefore unwilling to believe that morphine would fail to provide relief. Third, charges by several healthcare authorities that pain is inadequately treated have induced guilt among healthcare providers [1]. The ensuing recommendations suggested implicitly that drugs characterized by far greater efficacy were available (i.e., “strong” opioids) and insufficiently used. This fallacious argument has placed opioids on a pedestal, and most patients and healthcare providers (including nurses) believe that standard morphine dosages are necessarily far more effective than acetaminophen and,
of course, than placebos. The legitimacy of this belief, particularly regarding patients with noncancer pain, deserves discussion. 2. Morphine (except in very high dosages) is not more effective on average than acetaminophen, and sometimes even than placebos, in patients with noncancer pain The scarcity of high-quality studies (randomized, doubleblinded, and controlled versus a placebo or another analgesic such as acetaminophen) on the efficacy of step III analgesics is stunning, given the long history of widespread use and abuse of these drugs. For instance, in patients with sciatica, a single randomized trial has compared morphine to a placebo. Furthermore, in this trial, the difference in efficacy between morphine (10 to 90 mg/day; mean dosage, 62 ± 29 mg/day) and the placebo was only 7% [2]. Although the number of patients was small, this near-equivalence between morphine and the placebo probably discouraged further trials. 2.1. Acute noncancer pain
∗ Corresponding author. E-mail address: [email protected] (J.-M. Berthelot).
The above-mentioned trial [2] was done in patients with chronic sciatic pain. However, in several randomized doubleblind trials, intravenous (IV) morphine was not more effective
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than IV acetaminophen in relieving acute pain in emergencyroom patients. Thus, in 146 patients with renal colic treated by IV infusion, 1 g of acetaminophen was as effective as 0.1 mg/kg of morphine: the pain score decreases after 30 minutes were 43 and 40 mm, respectively (versus 27 mm with the placebo) [3]. IV paracetamol was more effective than IV morphine in a randomized trial of 73 patients with renal colic (64-mm versus 57-mm pain score decreases, respectively) [4]. Acetaminophen and morphine administered via patient-controlled analgesia for post-laparotomy pain showed little difference in efficacy, with a small early advantage of morphine that was no longer present after 4 hours [5]. Similar equivalence between IV acetaminophen and IV morphine in standard dosages has been reported in patients with musculoskeletal diseases. In 137 patients with acute low back pain, IV morphine (0.1 mg/kg) was not more effective than IV acetaminophen (1 g): the pain score decreases after 30 minutes were 67 mm and 65 mm, respectively [6]. In 55 patients with extremely intense acute limb pain (score > 7/10), pain relief was not different between 1 g of IV acetaminophen and 10 mg of IV morphine [7]. Similarly, morphine was only minimally effective in post-cholecystectomy patients, inducing a mean pain score decrease of only 0.5/10 between 9 and 12 hours after the procedure [8]. After knee or hip arthroplasty, morphine 60 mg/day was not better than a placebo in alleviating the pain or allowing rehabilitation initiation and was associated with significantly higher rates of vomiting and subsequent drug dependency (P < 0.0001) [9]. Considerably higher morphine dosages might produce greater pain relief compared to acetaminophen. However, no reviews assessing this possibility are available. As with chronic pain, most studies in acute pain used morphine-equivalent dosages that were substantial but did not exceed 90 mg/day [10]. The evidence collected on morphine can probably be extrapolated to the other step III analgesics and, with even greater reason, to other routes of administration than intravenous infusion, despite the absence of randomized trials. 2.2. Chronic noncancer pain Chronic pain has been the focus of a far larger number of trials, which have been assessed in Cochrane meta-analyses. A review of 31 studies of neuropathic pain provided some evidence that opioids might be slightly more effective than placebos, with a pain score decrease by at least one-third in 57% of patients taking morphine versus 34% of those taking a placebo [11]. The authors cautioned that the difference in efficacy should be viewed with circumspection, as several sources of bias were identified and no trial of strong opioids versus acetaminophen was available [11]. Another meta-analysis found no proof of efficacy of oxycodone (Oxycontin® , Oxynorm® ) used to treat diabetic neuropathy, postherpetic neuralgia, or fibromyalgia [12]. In contrast, adverse events were common. A Cochrane review included 15 studies of low back pain, of which only 6 evaluated strong opioids [13]. The results suggested small benefits of opioid therapy compared to a placebo in the short-term, with a greater effect on pain than on function, but no evidence of long-term efficacy. For instance, in a randomized double-blind trial comparing hydromorphone (Sophidone® ) to a placebo in patients with good opioid response and safety profiles, the difference in efficacy after 3 months was only 1.4/10 points, and the proportion of patients improved by at least 30% was only 61% with hydromorphone versus 43% with the placebo [14]. This effect of hydromorphone was similar to that of acetaminophen (which was not more effective than a placebo in a study of acute low back pain [15]). These data explain that the level of evidence supporting the efficacy of strong opioids (including morphine, hydromorphone [Sophidone® ], oxycodone [Oxycontin® , Oxynorm® ] and oxymorphone) in 1887 patients was characterized as only moderate in a Cochrane review [13]. Similarly, a systematic review of NSAIDs
and opioids in patients with chronic low back pain showed only modest effects of both drug classes, with greater efficacy of NSAIDs compared to opioids [16]. A recent systematic review of analgesic effects in osteoarthritis showed that opioids were not more effective than NSAIDs or duloxetine (Cimbalta® ) [16]. Oxycodone (Oxycontin® , Oxynorm® ) and hydromorphone (Sophidone® ) may be even less effective and not superior over a placebo [17]. Anesthesiologists in the US recently suggested a revision of current guidelines to explicitly indicate that the expected pain score decrease after 3 months of strong opioid therapy for noncancer pain was similar to that seen with NSAIDs and only about 0.8 to 1.2/10 points [18]. In patients with an inadequate response or escape phenomenon, a dosage increase is often the preferred option, as opposed to IV administration or switching to another opioid. When treating noncancer pain due to musculoskeletal disease, it remains unclear whether increasing the dosage to the levels used in cancer can provide a clinically meaningful improvement (usually defined as an at least 1.5-point pain score decrease), despite the long-term toxicity of step III analgesics. A randomized placebo-controlled trial of 103 patients with chronic low back pain assessed sustained-release morphine in titrated dosages of up to a mean of 78 mg/day (sufficient sedation or development of adverse events) [19] Although a mean pain score improvement of 44% was obtained, a 42% decrease in analgesic efficacy was noted after 1 month. Also in patients with chronic low back pain, the difference in efficacy between sustainedrelease oxycodone (Oxycontin® , Oxynorm® ) and a placebo was only 0.7/10 points (mean pain score decrease on a 100-mm scale, 55.9 ± 25.4 mm with oxycodone versus 48.6 ± 23.1 mm with a placebo), although the oxycodone dosage could be titrated up to 40 mg every 12 hours [20]. In the US, the current pressure to relieve pain by any means has led to an epidemic of high-dose opioid use in patients with noncancer pain [21]. Recent work has established that the vast majority of patients on high-dose strong opioids fail to experience significant decreases in pain intensity or remain very dissatisfied with the treatment, in particular due to the development of hyperalgesia and drug tolerance (which decrease the efficacy of strong opioids) [22]. Similar trends have been documented in Europe. In a recent study from Norway, 14,477 of 46,000 individuals reported chronic noncancer pain and, among them, 15% took opioids including 3% who took high-dose step III opioids continuously [23]. In this last subgroup, three-quarters of patients reported persistent severe or very severe pain. These data support the results of the meta-analyses indicating that efficacy is disappointingly low. 3. The efficacy of opioids may be greater against cancer pain, due to the use of higher dosages, but also declines over time Some cancer patients experience good outcomes. Thus, 50 to 65% survive for longer than 2 years or achieve a full recovery, and there are at least 12 million cancer survivors in the US [24]. However, most randomized trials of opioids involved short-term treatment, usually for 4 weeks. Consequently, their results lead to overestimation of long-term efficacy (since efficacy diminishes over time due to opioid-induced hyperalgesia and to drug tolerance) and to underestimation of toxicity [25]. 3.1. Initial efficacy of high-dose opioids In cancer pain, morphine is used in higher dosages of 25 to 2000 mg per day, with a mean of 100–250 mg/day (i.e., 2 to 4 times higher than in noncancer musculoskeletal diseases). Because physicians are biased to believe that morphine in these high doses is
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necessarily effective, no randomized placebo-controlled trials have been conducted in morphine-naive patients and very few have compared morphine to other analgesics [26,27]. The only randomized placebo-controlled trial was done in a small group of only 19 patients with a history of immediate-release morphine therapy [27]. The patients were switched to sustained-release morphine then to either a placebo or the previous dosage of immediaterelease morphine. At the end of the trial, the level of analgesia was not different between the group returned to immediate-release morphine and the group given the placebo [27]. The lack of placebocontrolled trials and the possibility of large improvements brought about by a placebo or Hawthorne effect or by anticancer treatments (radiotherapy and chemotherapy) preclude an evaluation of the potential contribution of opioids to the observed benefits [25,28,29]. In a randomized placebo-controlled trial of tramadol to treat cancer patients with presumably neuropathic pain, the pain score improvement after 1 month was 57% with tramadol (mean pain score decrease from 6.8 to 2.9) but was also 39% with the placebo (mean pain score decrease from 7.0 to 4.3) [30]. Nevertheless, a real short-term effect of high-dose opioid therapy seems highly likely, particularly with fentanyl (Durogesic® ). In breakthrough cancer pain, nasal transmucosal fentanyl was more effective than intermediate dosages of oral morphine [31]. Similarly, in chronic cancer pain, proof of efficacy seems stronger for fentanyl than for other opioids [24], although the magnitude of the effect is unclear. However, this slightly greater efficacy is obtained at the expense of faster dependency induction. As no placebo-controlled trials are available in patients with cancer pain, Cochrane reviews have focused on studies comparing several opioids. Design flaws are common, with the primary outcome measure in most cases being “satisfactory” analgesia [29]. A review of oral step III analgesic therapy including 62 trials in a total of 4241 patients showed that a mean pain score of about 3/10 was obtained in slightly less than one-third of the trials (18/62, 29%) [29]. A recent systematic review showed limited efficacy of opioids for relieving cancer pain, with substantial toxicity [32]. Furthermore, recent opioids such as oxycodone (Oxycontin® , Oxynorm® ) or hydromorphone (Sophidone® ) were not more effective than morphine [32]. Similarly, although several recommendations indicate that preference should be given to sustained-release forms, the six randomized trials that compared sustained-release to immediate-release opioids found no difference [33] in efficacy or adverse events, particularly addiction, both in noncancer pain and in cancer pain [34]. 3.2. The effectiveness of morphine declines over time Pain that recurs or increases despite continued opioid therapy may be due to cancer progression promoted by the immunosuppressive effect of high-dose opioids [35]. Published trials assessed only short-term outcomes and, consequently, missed this effect, as well as escape phenomenon, drug tolerance and, perhaps, opioid-induced hyperalgesia. These events can induce both an exacerbation of the pain and a need to increase the dosages, in some cases without consulting the physician. Urine drug testing in patients participating in clinical trials has been recommended to identify cases of abuse [36]. 4. Awareness of opioid-induced hyperalgesia is low among healthcare providers Patients with morphine tolerance, dependency, or hyperalgesia all report an increase in pain intensity and request higher dosages. However, the management strategy differs across these three situations. In patients with tolerance, the opioid gradually becomes
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less effective, and higher dosages are therefore required. Tolerance is difficult to differentiate from a disease flare in patients with rheumatic diseases. Switching among opioids has been suggested to decrease the impact of tolerance, but no meta-analyses have obtained convincing support for this strategy [37], which increases the risk of dependency by prolonging the opioid exposure. Dependency is a perceived need to increase the dosage, due to craving. The symptoms of dependency may be physical (shaking, sweating, tachycardia, hypertension, mydriasis, abdominal pain, muscle cramps, confusion, agitation, anxiety, depression) and/or psychological (withdrawal from usual centers of interest and social interactions, as the patient focuses on obtaining the drug). Dependency is the downside of the feelings of euphoria that can be generated by opioids, particularly when delivered intravenously or via other routes characterized by rapid absorption. When crushed or chewed, oxycodone (Oxycontin® , Oxynorm® ) may have an effect similar to that of heroin, and the same may be true of hydromorphone (Sophidone® ), with both drugs then becoming capable of inducing dependency after a single dose. The frequency of dependency varies according to the severity criteria used to define this condition. Only patients who seek medical advice because of dependency or regularly request dosage increases can be easily identified. The most pessimistic estimate was made by the National Center on Addiction and Substance Abuse at Columbia University in the US in 2005: among patients receiving opioid therapy for pain, 30% (15 million individuals) were believed to be dependent [38]. It is to be hoped that many of these patients had transient opioid abuse with episodes of physical dependency, as opposed to longterm psychological dependency. Support for this possibility comes from a study in patients with no history of substance abuse or opioid therapy who were started on oxycodone (Oxycontin® , Oxynorm® ): subsequent severe chronic dependency occurred in only 0.6% of cases (1 patient in 150) [39]. Nevertheless, in the US, this frequency translates into several tens of thousands of new cases of severe opioid dependency each year, and this is only a floor value. Far higher frequencies would no doubt be documented among patients with a history of addictive behaviors, who are more likely to use opioids as substitutes for other drugs and thus move easily from opioids to heroin [40]. Opioid-induced hyperalgesia is a paradoxical increase in pain intensity during long-term opioid therapy. This phenomenon is most common among drug abusers and in patients on high-dose opioids for long periods (generally more than 4 weeks). However, faster onset of opioid-induced hyperalgesia has been reported in patients with no history of drug abuse or opioid exposure [41]. A review of 27 randomized controlled trials of intraoperative analgesia comparing an opioid to a placebo showed that patients having unknowingly received high-dose opioids (chiefly remifentanil) during surgery reported worse postoperative pain than did patients given intraoperative placebo therapy (difference, 0.94/10 after 1 hour, 0.71/10 after 4 hours, and 0.3/10 after 24 hours), despite higher dosages of postoperative opioids [42]. Exposure to low-dose opioids may increase heat sensitivity [43] and, in experimental models, hyperesthesia can occur with very low dosages. This situation raises major diagnostic challenges with weaning symptoms and drug dependency. Opioid-induced hyperalgesia may develop in up to 25% of all patients on long-term opioid therapy [44]. Although this finding is probably applicable only to the use of dosages greater than 100 mg/d, opioid-induced hyperalgesia should be considered in patients with hyperpathia and allodynia, before the development of myoclonus or even seizures or delirium [40]. A diagnosis of opioid-induced hyperalgesia is particularly likely if the pain worsens after an increase in the opioid dosage. Switching among opioids (including methadone) or using NMDA receptor antagonists (dextromethorphan and ketamine) can diminish drug-induced hyperalgesia but may merely prolong
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the opioid exposure, thereby generating further drawbacks and risks. 5. Petition in the US to set ceiling morphine dosages and durations The “war against pain” launched two decades ago in the US has been described as similar to opening Pandora’s box, particularly by allowing nonanesthesiologists to administer potent anesthetics [45]. Clearly, this war has been lost by many patients: it is estimated to have caused 10,000 to 20,000 drug-overdose deaths in the US (and the many other adverse effects of long-term opioids also need to be considered [46,47]). This result is not surprising, since so-called “strong” opioids, although more toxic than hoped, induce limited benefits. The moderate relief they may provide after a marked dosage increase is often counterbalanced by secondary loss of effectiveness and, most importantly, by dependency, a rare but potentially devastating complication. The promise that complete pain relief was within reach set an unattainable target, thus probably inducing considerable frustration in the public, making most individuals less tolerant to pain, and increasing their tendency to catastrophize [48]. Anesthesiologists specialized in pain control have warned European countries to steer clear of the very bad example set by the US in this field [21], particularly when analgesic therapy is given without the detection and treatment of the cause of pain. Although acetaminophen [49] and NSAIDs also have limitations, a group of pain-control specialists and anesthesiologists in the US has issued a petition requesting restrictions to the use of step III analgesics in patients with noncancer pain, namely, not exceeding 100 mg of morphine-equivalent per day for no longer than 100 days [50]. 6. Conclusion The answer to the question asked at the beginning of this review is clear: the designation “strong” opioids is misleading if the word “strong” is intended to reflect analgesic potency. On the other hand, the toxicity of these drugs, which is severe in some cases (over 10,000 deaths per year in the US) [20] does warrant their classification as step III analgesics [51]. If other analgesics are truly ineffective, the use of “strong” opioids for short periods (<3 months) remains legitimate and even advisable, in particular because of the major placebo and Hawthorne effects that result from a strong belief in their efficacy [52]. Nevertheless, “strong” opioids have not consistently been proven more effective than acetaminophen or NSAIDs in relieving noncancer pain due to musculoskeletal diseases. Neither have “strong” opioids always been found superior over a placebo in a variety of conditions such as low back pain [53] or sciatica [2], despite widespread use [54]. Cannabis also has only moderate effects, with substantial toxicity as a major drawback [55]. The development of new analgesic classes or nonpharmacological approaches [56] is awaited impatiently by all rheumatologists, whose everyday practice involves striving to relieve patients from chronic pain. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Van Zee A. The promotion and marketing of OxyContin: commercial triumph, public health tragedy. Am J Public Health 2009;99:221–7. [2] Khoromi S, Cui L, Nackers L, et al. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain 2007;130:66–75.
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Please cite this article in press as: Berthelot J-M, et al. Strong opioids for noncancer pain due to musculoskeletal diseases: Not more effective than acetaminophen or NSAIDs. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.08.003