Prospects and challenges in opioid analgesia for pain management

Abstract

Pain is still one of the most prevalent and distressing symptom in patients with chronic pain. Opioids are the most potent existing analgesics available in clinical practice. However, they are not always effective, particularly in the non-cancer population. Alternately adverse effects may limit their analgesic activity. Several different drug-development strategies have attempted to reduce side effects by exploiting anatomic barriers to drug distribution and to provide different analgesic mechanisms, as in the case of the oxycodone–naloxone combination or tapentadol. New delivery systems have been developed for a more effective management of breakthrough pain. Pharmacogenetics could play a critical role in personalizing pain management in the future.

Key words::

• Breakthrough pain
• Cancer pain
• Chronic pain
• genetics
• Opioids

Pain is still inadequately managed in patients with chronic pain syndromes. Chronic pain of moderate to severe intensity occurs in 19% of adult Europeans, seriously affecting the quality of their social and working lives. Very few were managed by pain specialists and nearly half received inadequate pain management1. It has been reported that the adjusted prevalence of pain 24 months before death is 26%, and the prevalence remains flat until 4 months before death, then it increases, reaching 46% in the last month of life2. Approximately 70% of cancer patients will experience pain at some point during the progression of disease.

Opioids are the most potent existing analgesics available in clinical practice. It is argued that physicians should be encouraged to prescribe opioids because they are indispensable for the treatment of pain and suffering, because uncontrolled pain could have deleterious physical effects, and because persistent pain destroys people’s autonomy, dignity, and decision making capacity. However, while for cancer pain opioids are the indisputable cornerstone of pain management, in the non-cancer population many concerns have been raised in the last decade.

Opioid use in recent years has escalated, making opioids one of the most commonly prescribed medication classes. The many issues associated with this increased opioid use include the lack of evidence supporting their long-term effectiveness, escalating misuse of prescription opioids, and uncertainty about the frequency and severity of multiple, poorly characterized adverse drug events associated with long-term opioid use such as endocrine dysfunction, immunosuppression, and opioid-induced hyperalgesia3. Approximately 30–50%4,5 of patients are expected to positively respond to opioids. The rate of prescription opioid related overdose death increased substantially in the United States over the past decade. Among patients receiving opioid prescriptions for pain, higher opioid doses were associated with increased risk of opioid overdose death6. Thus, based on weak evidence and risk of abuse, opioids must be used with great restraint and caution in the non-cancer population5.

Analgesia can be achieved with different opioid dosages in individuals, as there is effectively no ceiling to their analgesic effect and the proportion of adverse effects that the patient can tolerate is usually the limiting factor of the dose used. As opioids are the most commonly used drugs, and patients with difficult problems are assumed to use this class of drugs, opioid responsiveness has been the principal focus of researchers.

There is an extremely large variability in responsiveness across patients and in the response that an individual may reveal over time. The broad range of responsiveness extends from patients who easily achieve analgesia, that is maintained with few dosage adjustments, to those who are completely unresponsive and experience no pain relief at doses associated with intractable adverse effects7. The need for opioid escalation may indicate an abrupt change in the underlying disease, or reveal a previously unknown complication, indicating a change in the relation between dose and response. There are, however, a series of factors which may play a role, including any process that reduces the efficacy of the current analgesic approach, the occurrence of tolerance, the appearance of intractable adverse effects and symptoms other than pain, type and temporal pattern of pain, individual pharmacogenetic factors, and primary psychological processes. Moreover, clinical reports suggest that opioids, intended to abolish pain, can unexpectedly produce abnormally heightened pain sensations, which are characterized by a lowering of the pain threshold, commonly known as hyperalgesia8. Such abnormal sensations have been described as being quantitatively different from normal pain sensation and differentially localized from the site of the original pain complaint. This could result in an exacerbation rather than an attenuation of excitatory behaviors. Although much experimental data exists to explain these clinical changes of opioid response, no data exist on how, when and why this occurs, or if it is a simple consequence of a progressive derangement of the central nervous system.

Pharmacogenetics may very well play a critical role in personalizing pain management in the future. Recent research has identified and characterized the important roles that genetic variability plays in clinical opioid therapy outcomes. Polymorphisms within the genes encoding opioid receptors affect the opioid response. Moreover, metabolic enzyme polymorphisms, as well polymorphisms in transport proteins, affect opioid metabolism9. In the future, personalized opioid treatment could lead to a better selection of optimal therapy, fewer adverse effects, better adherence to therapy regimens, and reduced health care costs. However, in a recent study in 2294 European cancer pain patients, variability in 112 single nucleotide polymorphisms (SNPs) in 25 candidate genes did not influence opioid doses. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed10. Epigenetics, which regards the heritable phenoytpes resulting from environment-caused changes in a chromosome without alterations in the DNA sequence, is an imminent research field that will complement genetics11.

Recent drug-development strategies

Several different drug-development strategies have attempted to reduce side effects by exploiting anatomic barriers to drug distribution and to provide different analgesic mechanisms.

Oxycodone–naloxone combination

Prevention of opioid induced constipation is considered to be a more effective strategy than merely treating it when it occurs. Laxatives do not address the opioid receptor-mediated mechanism of bowel dysfunction and do not provide sufficient relief. A number of pioneer studies have assessed the ability of oral immediate release naloxone also showing some evidence for slightly reduced analgesic efficacy, and intestinal withdrawal symptoms. A prolonged-release formulation could confer additional benefits ensuring continual antagonism and by reducing the risk of overburdening the hepatic enzymatic system responsible for its first-pass metabolism, thus reducing the risk of naloxone being systematically available with consequent loss of analgesic efficacy. A slow-release oxycodone–naloxone combination in a single formulation tablet has been assessed in non-cancer patients with chronic pain. The preparation provided effective pain relief with a reduction in opioid-induced constipation as well as the use of laxatives. The optimal ratio was 2:1. Only a minimal number of patients had cancer pain12. Thus, it is important to have more data on the cancer population who are at higher risk of constipation due to the large number of contributing factors, and require higher doses of opioids in comparison with the non-cancer population.

Tapentadol

Evaluation of a combined mechanism of action, μ-opioid receptor activation with norepinephrine reuptake inhibition has been undertaken to improve the therapeutic usefulness of opioid analgesics. Agents with the latter properties have been found to be particularly effective in neuropathic pain conditions and to potentiate the analgesic effects of opioids. Tapentadol is a centrally acting oral analgesic which possesses both mechanisms of action and has been shown to be efficacious in acute and chronic pain of diverse etiologies. Tapentadol has been reported to have similar efficacy compared with oxycodone, but a better gastrointestinal tolerability13. Possible advantages rely on less addiction potential and drug–drug interactions with agents affected by CYP activity or plasma protein binding. However, long-term studies in cancer patients with chronic pain are lacking. As with other opioids, tapentadol has potential for abuse.

New delivery systems: rapid onset opioids for breakthrough pain

Breakthrough cancer pain can be defined as an acute transient worsening of pain in patients who have a controlled baseline pain. The management of breakthrough pain requires drugs with a rapid onset, which cannot be achieved with oral morphine. Fentanyl is a highly potent opioid, enabling it to effectively treat the severe pain intensity pain that is characteristic of breakthrough cancer pain. Alternative delivery systems have been developed in the recent years and are considered an option for the management of breakthrough pain14. Fentanyl can be administered by a number of different routes, including transmucosal and sublingual15. After the pioneer product oral transmucosal fentanyl (OTFC) has been shown to be superior to placebo and oral morphine, a new generation of delivery systems have been developed, to improve availability through the mucosal barrier or to overcome some practical problems. The fentanyl buccal tablet incorporates a novel drug delivery platform, oravescent technology, which employs an effervescent reaction to enhance fentanyl absorption through the buccal mucosa and facilitate rapid systemic exposure to the analgesic. Subsequently, a sublingual formulation of fentanyl has been developed. This takes the form of a small tablet that is based on a mix of water-soluble carrier particles coated with a mucoadhesive agent and active drug particles. Finally, the intranasal administration route is an alternative with several benefits, including fast systemic penetration and potential for self administration, as well as acceptable to patients with dysphagia, nausea and vomiting, impaired gastrointestinal function, or salivary dysfunction16.

Transparency

Declaration of funding

SM declares no conflict of interest and has received no payment in preparation of this manuscript.

Declaration of financial/other relationships

The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.