On 2016 Jul 19, David Keller commented:

Is an opioid more toxic in extended-release than in immediate-release form, for the same total daily dose?

Ray and colleagues list a number of possible toxicities of opioids, and state that long-acting opioids (LAO's) "are of particular concern because the prolonged drug levels might increase toxicity." [1] This raises the question of whether chronic pain patients experience higher mortality due to the long-acting delivery system, and whether an equal daily dose of the same opioid would be safer if taken in divided doses of the immediate-release form. For example, a study comparing the mortality associated with extended-release oxycodone versus immediate-release oxycodone would answer the question of how much of the mortality associated with long-acting opioids in this study was due to the long-acting delivery of opioids versus the opioids themselves. Unfortunately, this study cannot answer that important question.

Ray et al cite a guideline that recommends long-acting opioids "for patients with frequent or constant pain", but which adds the provision: "Short-acting opioids may be used during the initial dose titration period of long-acting formulations and as rescue medication for episodes of breakthrough pain" [2] Another guideline states: "Short-acting opioids are probably safer for initial therapy [than LAO's] since they have a shorter half-life and may be associated with a lower risk of inadvertent overdose." [3] Both guidelines question the safety of initiating LAO's in opioid-naive pain patients and suggest that short-acting opioids (SAO's), taken only as-needed, might be inherently safer for initiating the treatment of chronic pain, at least until the patient has arrived at a stable opioid dosing regimen and developed some tolerance to its adverse effects.

eTable 6 in the Supplement to this study discloses that 96-97% of both the control group and the LAO group were currently taking any dose of SAO, but it is not possible to determine what percentage had been taking a stable total daily dose of SAO's long enough to have completed titration to efficacy and developed tolerance to harms such as respiratory depression. In other words, how much mortality was caused by premature treatment with LAO's of patients who had not taken SAO's long enough to complete dose titration and develop opioid tolerance?

References

1: Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain. JAMA. 2016 Jun 14;315(22):2415-23. doi: 10.1001/jama.2016.7789. PubMed PMID: 27299617.

2: McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001 May-Jun;8(3):181-6. Review. PubMed PMID: 11344385.

3: Chou R, Fanciullo GJ, et al. American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009 Feb;10(2):113-30. doi: 10.1016/j.jpain.2008.10.008. PubMed PMID: 19187889; PubMed Central PMCID: PMC4043401.

On 2016 Jun 17, David Keller commented:

"Long-Acting Opioids Increase Mortality in Patients With Chronic Noncancer Pain" - erroneous Practice Update headline

Through no fault of the investigators of this trial, the headline over the Practice Update summary of this study mistakes the association demonstrated in this observational study for causality, which can only be proved by means of a prospective, randomized, head-to-head interventional trial comparing long-acting opioids with other options for treating chronic non-cancer pain. Until such results are available, the headline should read:

Long-Acting Opioids Are Associated With Increased Mortality in Patients With Chronic Noncancer Pain

This distinction is important, and is a frequent cause of confusion in writers of headlines about clinical trials. Because serious therapeutic mistakes result from over-valuing observational data, it is important to correct these erroneous headlines. Here is the link to Practice Update, accessed on 6/17/2016, containing the erroneous headline:

http://www.practiceupdate.com/content/long-acting-opioids-increase-mortality-in-patients-with-chronic-noncancer-pain/40326/55/6/1#commentarea

The primary-care expert who discusses this study for Practice Update is Peter Lin MD,CCFP, who writes: "Long acting opioids increase death? This is an important question but one that we can’t ethically answer with a study. Imagine getting consent for this study? We are trying to see if these medications would kill you. So we could not ethically randomize patients to long acting opioids versus antiepileptic or antidepressant treatment and see who dies faster." This comment misses the most important question raised, but not answered, in this paper.

The authors list a number of possible toxicities of opioids, and state that long-acting opioids (LAO's) "are of particular concern because the prolonged drug levels might increase toxicity." This raises the question of whether chronic pain patients experience higher mortality due to the long-acting delivery system itself, and whether an equal daily dose of the same opioid would be safer if taken in divided doses of the immediate-release form. For example, a study comparing the mortality associated with extended-release oxycodone versus immediate-release oxycodone would answer the question of how much of the mortality associated with long-acting opioids in this study was due to the long-acting delivery of opioids versus the opioids themselves. Only by comparing an intrinsically short-acting opioid, such as oxycodone, with its extended-release form, in a head-to-head randomized study, can we isolate and quantify any increased harm of the extended-release delivery system itself. Such a trial would be ethical if the subjects were pain patients who are stable on a short-acting opioid and have been designated as appropriate candidates to switch to the extended-release form. The control group would delay that change for a month, while the intervention group would switch to extended-release immediately. Any difference in harms between these two groups during the first month could then be definitely attributed to the extended-release delivery system itself, because all other variables would be held constant, including the pain medication molecule.

Only a randomized, controlled, head-to-head trial, such as proposed above, can quantify the harms and benefits caused by the extended-release delivery of an opioid molecule as compared with the same total daily dose of the immediate-release form of the same opioid molecule. Answering this fundamental question is necessary before further comparisons can be interpreted, such as between opioid pain medications with differing intrinsic durations of effect, or comparisons between opioids and nonopioid pain treatments.

On 2016 Jun 17, David Keller commented:

"Long-Acting Opioids Increase Mortality in Patients With Chronic Noncancer Pain" - erroneous Practice Update headline

Through no fault of the investigators of this trial, the headline over the Practice Update summary of this study mistakes the association demonstrated in this observational study for causality, which can only be proved by means of a prospective, randomized, head-to-head interventional trial comparing long-acting opioids with other options for treating chronic non-cancer pain. Until such results are available, the headline should read:

Long-Acting Opioids Are Associated With Increased Mortality in Patients With Chronic Noncancer Pain

This distinction is important, and is a frequent cause of confusion in writers of headlines about clinical trials. Because serious therapeutic mistakes result from over-valuing observational data, it is important to correct these erroneous headlines. Here is the link to Practice Update, accessed on 6/17/2016, containing the erroneous headline:

http://www.practiceupdate.com/content/long-acting-opioids-increase-mortality-in-patients-with-chronic-noncancer-pain/40326/55/6/1#commentarea

The primary-care expert who discusses this study for Practice Update is Peter Lin MD,CCFP, who writes: "Long acting opioids increase death? This is an important question but one that we can’t ethically answer with a study. Imagine getting consent for this study? We are trying to see if these medications would kill you. So we could not ethically randomize patients to long acting opioids versus antiepileptic or antidepressant treatment and see who dies faster." This comment misses the most important question raised, but not answered, in this paper.

The authors list a number of possible toxicities of opioids, and state that long-acting opioids (LAO's) "are of particular concern because the prolonged drug levels might increase toxicity." This raises the question of whether chronic pain patients experience higher mortality due to the long-acting delivery system itself, and whether an equal daily dose of the same opioid would be safer if taken in divided doses of the immediate-release form. For example, a study comparing the mortality associated with extended-release oxycodone versus immediate-release oxycodone would answer the question of how much of the mortality associated with long-acting opioids in this study was due to the long-acting delivery of opioids versus the opioids themselves. Only by comparing an intrinsically short-acting opioid, such as oxycodone, with its extended-release form, in a head-to-head randomized study, can we isolate and quantify any increased harm of the extended-release delivery system itself. Such a trial would be ethical if the subjects were pain patients who are stable on a short-acting opioid and have been designated as appropriate candidates to switch to the extended-release form. The control group would delay that change for a month, while the intervention group would switch to extended-release immediately. Any difference in harms between these two groups during the first month could then be definitely attributed to the extended-release delivery system itself, because all other variables would be held constant, including the pain medication molecule.

Only a randomized, controlled, head-to-head trial, such as proposed above, can quantify the harms and benefits caused by the extended-release delivery of an opioid molecule as compared with the same total daily dose of the immediate-release form of the same opioid molecule. Answering this fundamental question is necessary before further comparisons can be interpreted, such as between opioid pain medications with differing intrinsic durations of effect, or comparisons between opioids and nonopioid pain treatments.

On 2016 Jul 19, David Keller commented:

Is an opioid more toxic in extended-release than in immediate-release form, for the same total daily dose?

Ray and colleagues list a number of possible toxicities of opioids, and state that long-acting opioids (LAO's) "are of particular concern because the prolonged drug levels might increase toxicity." [1] This raises the question of whether chronic pain patients experience higher mortality due to the long-acting delivery system, and whether an equal daily dose of the same opioid would be safer if taken in divided doses of the immediate-release form. For example, a study comparing the mortality associated with extended-release oxycodone versus immediate-release oxycodone would answer the question of how much of the mortality associated with long-acting opioids in this study was due to the long-acting delivery of opioids versus the opioids themselves. Unfortunately, this study cannot answer that important question.

Ray et al cite a guideline that recommends long-acting opioids "for patients with frequent or constant pain", but which adds the provision: "Short-acting opioids may be used during the initial dose titration period of long-acting formulations and as rescue medication for episodes of breakthrough pain" [2] Another guideline states: "Short-acting opioids are probably safer for initial therapy [than LAO's] since they have a shorter half-life and may be associated with a lower risk of inadvertent overdose." [3] Both guidelines question the safety of initiating LAO's in opioid-naive pain patients and suggest that short-acting opioids (SAO's), taken only as-needed, might be inherently safer for initiating the treatment of chronic pain, at least until the patient has arrived at a stable opioid dosing regimen and developed some tolerance to its adverse effects.

eTable 6 in the Supplement to this study discloses that 96-97% of both the control group and the LAO group were currently taking any dose of SAO, but it is not possible to determine what percentage had been taking a stable total daily dose of SAO's long enough to have completed titration to efficacy and developed tolerance to harms such as respiratory depression. In other words, how much mortality was caused by premature treatment with LAO's of patients who had not taken SAO's long enough to complete dose titration and develop opioid tolerance?

References

1: Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain. JAMA. 2016 Jun 14;315(22):2415-23. doi: 10.1001/jama.2016.7789. PubMed PMID: 27299617.

2: McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001 May-Jun;8(3):181-6. Review. PubMed PMID: 11344385.

3: Chou R, Fanciullo GJ, et al. American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009 Feb;10(2):113-30. doi: 10.1016/j.jpain.2008.10.008. PubMed PMID: 19187889; PubMed Central PMCID: PMC4043401.