Oxycodone–naloxone prolonged-release tablets

Leuven Centre for Algology and Pain Management,

Anesthesiology and Algology,

University Hospitals Leuven,

Department of Cardiovascular Sciences,

KU Leuven, Belgium

Email: [email protected]

Chronic pain is a major healthcare problem. It is accepted as a biopsychosocial phenomenon and unless all aspects of a patient’s pain are dealt with appropriately and simultaneously, the overall effectiveness of treatment will be poor. Pharmacological approaches play an important part in the integrated care for chronic pain patients but need to be placed into a broader framework including interventional procedures and multimodal strategies. Pharmacological agents for the management of chronic pain include paracetamol, non-steroidal anti-inflammatory drugs, antidepressants and opioids, among others.(1)

Opioids are among the strongest analgesics available. Successful treatment depends on achieving a good balance between analgesia and adverse events. Opioids act as analgesics, mainly by activating m-receptors in the central nervous system; however, activation of these receptors in the enteric nervous system leads to a range of gastrointestinal symptoms of which constipation is the most common and bothersome.

Large-scale studies of gastrointestinal side effects in patients receiving opioid therapy indicate that opioid-induced constipation (OIC) affects 57–81% of individuals, and in patients with cancer, the prevalence is greater (up to 95% of individuals affected). Patients very rarely develop tolerance to the constipating effects of opioids. Patients also report that constipation and other symptoms of opioid-induced bowel dysfunction (OIBD) have at least a moderately negative impact on quality of life and impair activities of daily living.(2)

OIBD develops in nearly all patients, so preventive measures are necessary from the beginning of treatment. The main approach to dealing with OIC is to combine general measures (verbal and written patient information, stimulation of fluid intake, general exercise and dietary measures) with the use of a laxative. The routinely prescribed laxative regimen includes a combination of drugs with predominantly stool softening, osmotic or stimulant properties; however, patients often report such treatment to be unsatisfactory in OIC. There is no consistent evidence from randomised, controlled trials to suggest one particular laxative is most effective at managing symptoms of OIC.

One strategy is the systemic use of opioid antagonists that do not cross the blood–brain barrier. These peripherally-acting µ-opioid receptor (MOR) antagonists should enable a reduction of OIC by targeting the MOR receptors in the gastrointestinal tract while preserving the analgesic activity of concurrently administered opioid analgesics.(3) Because of its polarity, methylnaltrexone does not cross the blood–brain barrier and has been approved for the treatment of OIC in patients with advanced illness. However, a major drawback is the requirement for subcutaneous administration and its high costs. Similarly, alvimopan does not cross the blood–brain barrier because of its large molecular weight and polarity.

Another strategy is the use of an opioid antagonist with local effects in the gut (for example, naloxone).

OIC and other symptoms of OIBD are mediated predominantly by enteric μ-opioid receptors, so selective blockade of these receptors could improve the side-effect profile of opioid analgesics without compromising analgesia. Naloxone is a µ-opioid receptor antagonist with a proven long-term safety profile. Intravenous naloxone rapidly crosses the blood–brain barrier and is indicated for the treatment of opioid-induced respiratory depression. Oral naloxone was initially investigated as an immediate-release formulation in combination with opioid analgesics. This combination improved bowel function and reduced laxative use in patients with chronic pain. However, some patients exhibited symptoms of systemic opioid withdrawal or reversal of opioid analgesia. It was hypothesised that the immediate-release formulation of naloxone led to saturation of hepatic enzymes responsible for its metabolism, thereby increasing the risk of systemic antagonism. It was postulated that this might be avoided by a prolonged-release formulation.4 When administered orally as a prolonged-release tablet, the bioavailability of naloxone is ≤2%. This is due to extensive first-pass hepatic metabolism, and consequently the effects of oral prolonged-release naloxone are principally confined to the gastrointestinal tract.(4)

A fixed combination of oxycodone–naloxone prolonged-release is available in many countries.

Oxycodone–naloxone prolonged-release tablets combine the centrally acting opioid analgesic, oxycodone, and peripherally acting naloxone in a single tablet. The aim is to combine the analgesic benefits of oxycodone with continual blockade of opioid receptors in the gastrointestinal tract, thereby preventing onset of OIC.(5) This is in contrast to the rationale for prescribing laxatives in conjunction with opioid analgesics as an attempt at addressing the symptoms of OIC. Based on the pharmacological principles and, importantly, the clinical data, the beneficial effects of oxycodone–naloxone prolonged-release tablets in terms of reducing gastrointestinal side effects are caused by the local targeted action of naloxone. This occurs not only in the colon but also in the small intestine. In a study of healthy volunteers, the prolonged-release tablets normalised the delayed arrival of 99mTechnetium-labelled tablets into the colon that was observed with oxycodone alone. Together, these observations also confirm that opioids impart significant effects throughout the gastrointestinal tract, providing rationale for a treatment to address opioid-induced constipation which is not focused mainly on the colon.

A phase III clinical trial programme has demonstrated that treatment with oxycodone–naloxone prolonged-release at doses up to 80mg/day provides effective analgesia comparable to prolonged-release oxycodone for patients with chronic non-malignant pain.(6–11) These studies also showed that this treatment is associated with less frequent use of laxatives and clinically meaningful improvements in symptoms of OIC compared with oxycodone alone, as demonstrated by a number of parameters, including Bowel Function Index scores.

Further studies have also investigated oxycodone–naloxone prolonged-release tablets in patients with cancer pain at doses of up to 120mg/day.(12,13) Observations were similar to those reported in patients with non-malignant pain.(12) An open-label study in palliative care cancer patients indicated that oxycodone–naloxone prolonged-release was associated with clinically relevant improvements in pain intensity and bowel function, as well as with increased patient satisfaction.(13) Findings from these clinical studies are supported by a large, observational, four-week study of 7836 patients receiving oxycodone/naloxone prolonged release tablets for severe cancer- and non-cancer-related pain. The treatment was associated with good analgesia and significantly reduced constipation and other opioid-induced gastrointestinal side effects. A recent analysis examining quality-of-life benefits and treatment cost in patients with non-cancer pain and OIC found oxycodone/naloxone prolonged-release tablets to be a cost-effective treatment option.(14)

Given the nature of chronic pain, effective management strategies often necessitate prolonged therapy. The results of 52-week open-label extension studies of phase III trials of the long-term effects of treatment with prolonged-release tablets have been published.(10) In these open-label extension studies, over 78% of patients completed 52 weeks of treatment, approximately half of whom had already received 12 weeks of therapy with prolonged-release tablets in the preceding double-blind, randomised phase of the trials.(10) A pooled analysis of two extension-phase trials revealed pain control was maintained throughout the 52-week treatment periods. Improvement in bowel function persisted throughout the study, and was particularly marked in patients who switched from oxycodone to the oxycodone–naloxone combination in the double-blind studies. Fewer than 10% of patients received laxatives regularly during the study. The safety profile and Subjective Opioid Withdrawal Scale scores were consistent with the 12-week studies.(6,7) These findings are consistent with the second report of 52-week treatment with prolonged-release tablets in extension trials of phase III studies.(10)

OIC can hamper optimal analgesia with opioids in moderate-to-severe pain despite the use of laxatives.

Oxycodone–naloxone prolonged-release tablets combine the centrally acting opioid analgesic, oxycodone, and naloxone, which has demonstrated peripheral antagonism throughout the gut. An extensive clinical trial programme in patients with moderate-to-severe chronic cancer-related and non-cancer-related pain has demonstrated that this treatment provides effective analgesia and is associated with significantly improved bowel function. Furthermore, the effect of the treatment is maintained during long-term therapy. These findings indicate that a treatment with a mechanism of action aimed specifically to target the unique aetiology of OIC can prevent such symptoms without impacting on the effective analgesia afforded by opioids.

• Opioids are a cornerstone in the pharmacological management of pain. Adverse events, including opioid induced constipation (OIC), can limit effective treatment.
• General preventive measures and laxatives are often unsatisfactory in the management of OIC.
• New mechanistic strategies include the use of opioid antagonists, including methylnaltrexone, alvimopam and naloxone.
• Oxycodone–naloxone prolonged-release tablets combine the centrally acting opioid analgesic, oxycodone, and naloxone, which has demonstrated peripheral antagonism throughout the gut.
• An extensive clinical development program me with oxycodone-naloxone prolonged-release tablets demonstrated effective analgesia, less frequent use of laxatives and clinically meaningful improvements in the symptoms of OIC.

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