Efficacy and safety of dual opioid therapy

Abstract

There is some evidence for a partial opioid switching or an ‘add on’ approach to opioid dosing strategies. Preclinical and clinical findings suggest different activation profiles for the stimulation of the mu subtypes, raising the questions about what might occur with combinations of these substances. In the postoperative setting, it seems that the analgesic effect of the combination at equivalent doses is similar to that produced by the individual components, not adding particular advantages. However, adverse effects seem to be reduced with the combination of morphine/oxycodone, when given in doses equianalgesic to individual opioids. The reduction of opioid-induced postoperative adverse effects may have important clinical implications, given that adverse effects may prolong length of stay and hospitalization costs. Thus, in the acute postoperative setting, a reduction of adverse effects may be expected. In chronic pain, information is still in the infancy, but opioid combination therapy may have greater advantages in improving the opioid response. The possibility to clinically translate opioid combinations into practice, as demonstrated in some animal models, depends on a broad number of factors implicated in the pain process. More research is needed to better elucidate these issues in the near future.

Keywords::

• adverse effects
• dual therapy
• opioid combination
• opioid receptor opioid switching
• tolerability

1. Introduction

Opioids remain the most effective systemic analgesics available for moderate to severe acute and chronic pain. The mechanism of action and pharmacology of opioids is complex. Opioids considered to be highly mu-selective still bind to a large number of μ-opioid receptor subtypes, with the various opioids producing subtly different pharmacological response based on the distinct activation profiles of the mu receptor subtypes. The use of opioids is often limited by a frequent occurrence of adverse effects. The development of adverse effects is of paramount importance for the treatment of chronic pain with opioids [1].

The idea of combining one opioid with another opioid to reduce the development of adverse effects, or eventually to augment analgesia, is a relatively new concept [2]. Although each opioid receptor can mediate its effect independently, a growing body of evidence has been accumulating for the existence of cellular or molecular interaction among opioid receptor types. Multiple distinct opioid receptor subtypes have been identified and interactions between them may change the opioid response [3]. Opioid μ receptor agonists have been used to form multitargeted directed ligands, which in animal models improve the therapeutic index of the analgesic relative to monovalent potent μ-receptor agents [4]. Receptor subtypes are likely to be receptor dimers able to alter signaling and trafficking of receptors relative to monomers [5]. Different opioids produce different effects through unique conformational changes of the opioid receptor [6]. They include, for example, differences in G-protein interactions, receptor phosphorylation, and β-arrestin activity [7]. As a consequence, allosteric modulation, ligands signaling bias, and mu opioid receptor subtypes or dimmers may contribute for giving a rationale to opioid combination in an attempt to improve the clinical response [3,8,9].

Experimental studies in animals that have examined administration of opioid combinations have concluded that there is either a synergistic effect or an additive effect on analgesia and a lowering of opioid-induced adverse effects [10]. For example, behavioral antinociceptive and cross-tolerance studies indicated that pain-relieving effects of oxycodone are mediated by putative k-opioid receptors, and an isobolographic analysis revealed marked antinociceptive synergy between these two drugs [11]. In vivo studies documented that oxycodone does not desensitize G-protein-activated inwardly rectifying potassium currents, suggesting that it may interact with a different population of opioid receptors or modulate opioid receptor signaling in a subtly different way from other opioids [8]. The effects of oxycodone and morphine have been found to be modulated differently in experimental models of bone cancer pain [12]. These aspects remain controversial, as observations reported could be influenced by several factors, including localization of receptor subtypes in specific tissues and drug administration route, dose, and regimen [13-15].

Controversial data have been found in humans in both acute and chronic pain. Intravenous morphine given as patient-controlled analgesia plus oral oxycodone was compared with the same treatment and saline in patients undergoing lumbar discectomy. Pain scores significantly improved and morphine consumption was reduced in comparison with placebo. Moreover, the incidence of nausea and vomiting, and the time to first bowel movement were significantly improved with the combination [16]. Patients with postoperative pain following bunionectomy surgery were randomized to receive placebo or ascending doses of morphine-oxycodone combination during a 48-h period. A significant improvement in the proportion of responders was observed with each morphine/oxycodone dose compared with placebo. Nausea and pruritus were more frequently reported in the group receiving the combination in different doses, while minimal or no changes in respiration rate and blood saturation were observed [17].

Patients were randomized to receive oral morphine and oxycodone combination in different doses and individual components in morphine equivalent doses after bunionectomy. The combination produced superior analgesic effects when compared with its individual components, but comparable efficacy when compared with its morphine equivalent doses. The proportion of patients with at least one adverse effect treated with 12/8 mg morphine/oxycodone combination and with individual components, morphine 12 mg and oxycodone 8 mg, were similar. This phenomenon was also observed with the lower doses. Adverse effects were lower, reduced at least 50%, in the combination groups compared with its morphine-equivalent doses. Similar findings were observed for nausea and vomiting [18].

Intravenous morphine and the combination with oxycodone were assessed in patients who underwent total hip replacement. Although no significant differences in pain intensity were observed, patients who received the combination were able to achieve better pain relief using fewer patient-controlled analgesia. The overall incidence of adverse effects was comparable between the groups. The severity of nausea and vomiting, however, was lower with morphine–oxycodone combination, and the incidence of oxygen desaturation was higher in patients receiving morphine only [19]. Flexible doses of morphine–oxycodone combination were superior to low-dose morphine/oxycodone but comparable to oxycodone/acetaminophen in patients operated for arthroplasty. Gastrointestinal events in patients receiving the opioid combination were less than one third that in oxycodone/acetaminophen control arm, but oxygen desaturation occurred more frequently in the morphine/oxycodone flexible group [20]. The combination resulted more effective than individual drugs in reducing the pain intensity after bunionectomy compared to its individual components, with fewer subjects requiring rescue medication, also reporting a longer time to first use of rescue medication. However, adverse effects and oxygen desaturation occurred at a higher rate with the combination [21].

Few trials assessed the opioid combination in chronic pain, despite that multiple opioids are often simultaneously administered for different reasons in the clinical setting. In patients with chronic pain due to osteoarthritis, the addition of tramadol resulted in a decrease in opioid doses with fewer adverse effects. The addition of tramadol also produced less gastrointestinal adverse effects, although sweating was more likely to occur, in comparison with patients treated with opioids alone [22]. In cancer patients, patients treated in a cross-over study with controlled-release morphine or controlled-release oxycodone, and immediate-release morphine when the pain increased, those receiving controlled-release oxycodone and immediate-release morphine as needed required 38% less morphine than patients receiving morphine preparations. Moreover, they experienced significantly less nausea and vomiting [23]. The administration of small doses of a second opioid in patients with an unfavorable response during escalation with the prior opioid, lower increases of equivalent doses of the second opioid, < 20%, provided a better analgesia. Global opioid escalation index calculated in the following weeks after starting the treatment was maintained at low levels. The relatively low doses of the second opioid administered did not produce adverse effects of significant intensity [24]. Tramadol, added to transdermal fentanyl, provided pain control with slower dose escalation of fentanyl in comparison with patients receiving conventional increasing doses of fentanyl. No significant differences in adverse effects were reported [25].

2. Expert opinion

According to the existent studies, the use of an opioid combination remains a controversial issue, although this practice has become more commonplace. One of the requirements for marketing approval of a drug is that milligram components when combined enhance the safety or effectiveness of the principle active component. The basic premise of an analgesic combination is that the two drugs operate through different mechanisms of action, so that the combination may result in a reduction in dose-related adverse effects. The accumulated bench research over the past decade provides a rationale for considering clinical trials of opioid combination [4,26].

In the postoperative setting, it seems that the analgesic effect of the combination at equivalent doses is similar to that produced by the individual components, not adding particular advantages. However, adverse effects seem to be reduced with the combination of opioids given in doses equianalgesic to individual opioids. The reduction of opioid-induced postoperative adverse effects may have important clinical implications, given that adverse effects may prolong length of stay and hospitalization costs [27]. Thus, in the acute postoperative setting, a reduction of adverse effects may be expected. This observation suggests that the topic is worthwhile of further scientific considerations.

In chronic pain, information is still in the infancy, but might potentially have better advantages in improving the opioid response. Unfortunately, at this time, it is not possible to accurately predict the optimal combination in a specific patient, as data regarding sequential or simultaneous dosing schedule, dose levels, or equianalgesic ratios are poorly available. Moreover, pain phenotype may be an important factor, which has never been explored in this context. Adverse effects should be closely monitored as data about the influence of dual opioid therapy on adverse effects are limited. At the moment, only a weak recommendation can be used to support combination opioid therapy. This is based on the caveat that the desirable effects of combination therapy are outweighed by any disadvantages that this would confer [28]. Attempts to clinically translate opioid combinations into practice as demonstrated in some animal models may fail due to the broad number of factors implicated in the pain process. There are some areas of research that need to be explored in the next future. The analgesic benefits of an opioid combination will probably depend on both the pain phenotype and the state of the central nervous system. Sequential or simultaneous dosing schedules, dose levels, or equivalence ratios for achieving the best outcome need to be assessed. Adverse effects or the need for dose escalation should be evaluated in long-term studies of a large number of patients, as at the moment the knowledge on this subject is really poor.

Declaration of interest

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.