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Written by

Dr Fausto Morell-Ducós Dr Fausto Morell-Ducós is a clinical pain fellow at St Bartholomew's Hospital, London, UK

Dr Saowarat Snidvongs Dr Saowarat Snidvongs is a consultant in pain management, St Bartholomew's Hospital, London, UK

The abuse potential of opioid formulations

Published 12 August 2016

Dr Fausto Morell-Ducós and Dr Saowarat Snidvongs discuss formulations with abuse deterrent properties and the development of abuse-resistant formulations

Key learning points

  • An increase in the use of opioids in the management of chronic non-cancer pain has been accompanied by an increase in opioid abuse.
  • Modified-release opioids achieve more constant levels above a minimally effective concentration.
  • Formulations with abuse-deterrent properties can limit the ability of abusers to alter the modified-release pharmacokinetic profile.

The use of opioids in the management of chronic non-cancer pain (CNCP) has increased significantly over the past 25 years in the US. This has been accompanied by an increase in addiction and related disorders as well as overdose-related deaths.1 Similarly, studies indicate that rates for opioid prescriptions in CNCP have also increased in European countries over the last decade.2,3

This increase in opioid prescription in the US arose as a result of an increasing perception that the risk of addiction and dependence in patients treated long-term with controlled-release opioid formulations was relatively low, in spite of the lack of any clear evidence from clinical trials.4 There was, however, a concomitant increase in mortality rate from accidental poisoning4 that has been associated with the introduction of modified-release (MR) opioid preparations in some regions.5,6

The prevalence and incidence of abuse varies significantly according to setting, population characteristics, frequency of opioid prescription and the specific opioids and dosages used. Although there are very few large-scale epidemiological studies that examine the risk of developing physical dependence and addiction with chronic opioid therapy, it is likely that this occurs in more patients than previously reported.4

It is estimated that opioid use disorders are four times more likely to occur in those receiving opioid therapy than in the general population,7 and 50% of patients taking opioids for at least three months are still taking opioids five years later.4

Although the increasing concern regarding the use of opioid therapy in CNCP has resulted in reluctance from some practitioners to prescribe opioids long-term, it often remains the only viable treatment option in patients with chronic pain who require sustained daily analgesia. A greater understanding of the pharmacokinetics (PK) and other properties of frequently prescribed MR opioids and novel formulations is needed, in order to allow an informed discussion regarding their use and safety profile.

The opioids frequently used to manage chronic pain in this setting include extended-release formulations of morphine, oxycodone, tapentadol, hydromorphone and oxymorphone; as well as transdermal buprenorphine and fentanyl. Data obtained from the Poison Center Program via the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System, which was developed to provide postmarketing surveillance of prescription drug abuse and diversion in the US,8 showed that rates of abuse for a 24-month time period between July 2009 and June 2011 were highest for hydrocodone, followed by oxycodone, tramadol and tapentadol immediate release (approximately 1.78–2.02, 1.00–1.18, 0.63–0.76 and 0.003–0.02 per 100,000 population, respectively).8

Pharmacokinetics and clinical effects

It is generally accepted that there is a relationship between opioid plasma levels and their clinical effects, justifying the use of MR preparations to achieve more constant levels above a minimally effective concentration.9 The diminished number of fluctuations in the PK profile of these MR formulations also results in a lower abuse quotient (a longer Tmax and a lower Cmax), provided they are not tampered with.10

Other drug properties that facilitate abuse of opioids include duration of effect and ease of extraction of the active compound from MR formulations (using tablet manipulation such as crushing, snorting or extraction for injection).11 This is a particular concern in view of the large doses of active compound contained in single MR tablets and the prolonged elimination half-lives involved.

As a result, formulations with abuse-deterrent properties have been developed which limit the ability of abusers to alter the MR PK profile, or which reduce absorption once the tablet has been tampered with. These include:

  • Tablets that are more difficult to grind into a fine powder or to dissolve.
  • Tablets that maintain their MR properties after being crushed.
  • Tablets that contain additional compounds which, once manipulated, make the product less able to cause a reward (for example, by including an antagonist which only becomes bioavailable once the integrity of the tablet has been mechanically breached).

Although these formulations may decrease consumption in patients who abuse opioids to obtain a recreational ‘high’, they may not have this effect in those who consume drugs in ways not prescribed as a result of unsatisfactory pain control, or in order to diminish symptoms of poorly controlled co-existing conditions such as anxiety or depression.

Conclusion

The use of opioids in the treatment of CNCP provides a much-needed answer to the otherwise unmet need of daily, sustained analgesia in this large patient population, but diversion and abuse are frequent events associated with significant morbidity and mortality. The increasing development of formulations with abuse-deterrent properties appears to offer a potential solution to this problem. Multiple preparations are currently being developed, and there are data to indicate that such opioid formulations with barriers to tampering do result in reduced rates of abuse.12 There remains, however, the potential for existent opioid abusers to subsequently switch to non-abuse-resistant formulations, resulting in unintended increases in the rates of misuse of these products. This has, indeed, been observed.13 The long-term effect of the widespread introduction of these formulations at a population level is therefore yet to be determined.

  • Dr Fausto Morell-Ducós is a clinical pain fellow and Dr Saowarat Snidvongs is a consultant in pain management, St Bartholomew's Hospital, London

Date of preparation: August 2016; MINT/PAEU-15001v