We thank Dr Vozoris for his insightful comments on our paper. (1)
The use of opioids for treating pain and the underlying evidence base for this indication was not the scope of our article. Although we agree that the evidence for treatment with opioids for "chronic" musculoskeletal pain is inconsistent or weak, we had insufficient data to determine symptom severity and whether the patients were prescribed opioids for chronic or acute pain. It should also be considered that the cited Cochrane reviews on opioids for chronic pain have weak evidence for their conclusions. (2,3) The review of long-term effectiveness and safety of opioid therapy for chronic noncancer pain by Noble et al (2) included 25 case series and only 1 randomized controlled trial. The clinician should carefully weigh the risk versus benefit of opioids in pain treatment, especially in the setting of clinical instability and in chronic pain. However, we think that there are many situations where opioids have an important role in treating severe distressing pain, where failure to use opioids might contribute to unnecessary suffering and treatment nihilism.
The majority of patients had World Health Organization (WHO) functional class 1 or 2 in our study and Dr Vozoris suggests that their respiratory symptoms may have been relieved by more traditional COPD management and that symptomatic treatment with opioids was simply not required. There are strong data to disagree with this statement. These patients had end-stage COPD with chronic respiratory failure with a median survival time of 1.9 years. (4) Breathlessness is very common in patients with very severe COPD (5) and a high proportion of patients suffer from chronic breathlessness, despite intensive COPD treatment. (6) In a recent study of less severely ill COPD patients, chronic breathlessness that significantly compromised function was present in 74% of patients, despite combined inhaled triple therapy and physiotherapy. (6) Given the evidence base for the efficacy of low-dose opioids for safely reducing chronic breathlessness, our finding that only 2% of opioid prescriptions were for breathlessness strongly supports the assertion that there is systematic undertreatment of people with chronic breathlessness and advanced COPD.
Data on the dispensed opioid doses are presented in Table 2 as WHO defined daily doses per prescription. (1) More details regarding dispensed doses at the time of starting long-term oxygen therapy have been published separately. (7) The average dispensed prescription in this study was for short-term treatment of a mean of 9.3 (interquartile range, 3.7-16.7) defined daily doses of morphine equivalents in milligrams of morphine per prescription.
Low-dose sustained release oral morphine is the pharmacological treatment with the best evidence base for relieving chronic breathlessness in advanced COPD, and the risk of serious adverse events (respiratory depression, hospitalization, or death) does not seem to increase by low-dose morphine in the short term. (8) The observational, registry-based study by Vozoris et al reported increased respiratory-related morbidity and mortality among COPD patients receiving incident opioids. The 30-day mortality risk was 1.9% versus 1.1% in people without an opioid prescription after propensity score matching; an absolute difference of 0.8% in a population where the prescription likely was for symptom control in relation to clinical deterioration and late in life where increased risk of death was the expected outcome. (9) Furthermore, stronger opioids were associated with "lower" risk than weaker opioids and information was lacking on prevalence and severity of symptoms, degree of clinical safety, and why, how, or at what dose the opioid was used. (9) In a previous analysis in patients with oxygen-dependent COPD, treatment with opioids in low doses ([less than or equal to]30 mg opioid equivalents per day) was not associated with increased risk of hospitalization or death. (7)
We commend Vozoris et al for taking forward high-quality safety studies in this important area. Combined efforts are needed to further determine the suitable target population and clinical net benefit of low-dose opioids for symptomatic control in patients with severe illness.
The authors report no conflicts of interest in this communication.
(1.) Ahmadi Z, Bernelid E, Currow DC, Ekstrom M. Prescription of opioids for breathlessness in end-stage COPD: a national population-based study. Int J Chron Obstruct Pulmon Dis. 2016;11:2651-2657.
(2.) Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010(1):CD006605.
(3.) Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC. Opioids compared to placebo or other treatments for chronic low-back pain. Cochrane Database Syst Rev. 2013;(8):CD004959.
(4.) Ahmadi Z, Sundh J, Bornefalk-Hermansson A, Ekstrom M. Long-term oxygen therapy 24 vs 15 h/day and mortality in chronic obstructive pulmonary disease. PLoS One. 2016;11(9):e0163293.
(5.) Blinderman CD, Homel P, Billings JA, Tennstedt S, Portenoy RK. Symptom distress and quality of life in patients with advanced chronic obstructive pulmonary disease. J Pain Symptom Manage. 2009;38(1): 115-123.
(6.) Sundh J, Ekstrom M. Persistent disabling breathlessness in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2016;11:2805-2812.
(7.) Ekstrom MP, Bornefalk-Hermansson A, Abernethy AP, Currow DC. Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective study. BMJ. 2014;348:g445.
(8.) Ekstrom M, Nilsson F, Abernethy AA, Currow DC. Effects of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease: a systematic review. Ann Am Thorac Soc. 2015;12(7): 1079-1092.
(9.) Vozoris NT, Wang X, Fischer HD, et al. Incident opioid drug use and adverse respiratory outcomes among older adults with COPD. Eur Respir J. 2016;48(3):683.
Zainab Ahmadi (1)
David C Currow (2)
Magnus Ekstrom (1,2)
(1) Department of Clinical Sciences, Division of Respiratory Medicine and Allergology, Lund University Hospital, Lund, Sweden; (2) Discipline, Palliative and Supportive Services, Flinders University, Adelaide, SA, Australia
Correspondence: Zainab Ahmadi
Department of Clinical Sciences, Division of Respiratory Medicine and Allergology, Lund University Hospital, Klinikgatan 18, SE-221 00 Lund, Sweden
Tel +46 46 17 1000