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NSAIDs relieve osteoarthritis (OA) pain, but cardiovascular safety in question even for diclofenac, ibuprofen, naproxen, and celecoxib: what are the alternatives?
Scandinavian Journal of Pain 16 (2017) 148–149
Contents lists available at ScienceDirect
Scandinavian Journal of Pain journal homepage: www.ScandinavianJournalPain.com
Editorial comment
NSAIDs relieve osteoarthritis (OA) pain, but cardiovascular safety in question even for diclofenac, ibuprofen, naproxen, and celecoxib: what are the alternatives? Harald Breivik a,b,c,∗ a
University of Oslo, Faculty of Medicine, Oslo, Norway Oslo University Hospital, Department of Pain Management and Research, Oslo, Norway c Oslo University Hospital, Department of Anaesthesiology, Oslo, Norway b
Citing the excellent editorial comment by Pekka Mäntyselkä 10 years ago in PAIN on the “Balancing act with geriatric pain treatment”, World Health Organisation predicts that there will be 1.2 billion people above 60 years by 2025, 2 billion by 2050, and in the developed world the very old, aged 80+, is the fastest growing population group. Persistent pain, due to degenerative diseases, osteoarthritis (OA) in particular, becomes more prevalent as a person ages [1]. Comorbidities and polypharmacies increasingly pose dilemmas with increasing risks of interactions and serious side effects. Pain and dysfunction from OA are poorly relieved [2], but NSAIDs (traditional tNSAIDs and COX-2 specific inhibitors – COXIBs) are still recommended as cornerstones in the pharmacological treatment of OA [3]. In this issue of the Scandinavian Journal of Pain Patricia Guyot and her co-workers with senior author Andrew Moore, publish an interesting network meta-analysis of diclofenac, ibuprofen, naproxen, indomethacine, and piroxicam for osteoarthritis pain [4]. They analyzed data from 29 previously unpublished randomized, controlled (double-blind) trials (RCTs) from the time before the specific COX2-inhibitors appeared and before cardiovascular risks of traditional NSAIDs and the COXIBs were recognized. A network meta-analysis is possible when one drug is compare with placebo and another active drug, and one of these drugs is compare with a third drug in another RCT, and so on, and so on. In a Bayesian network meta-analysis, they compared efficacy and safety of several tNSAIDs [4]. They used changes in VAS-intensity of pain and patients’ global assessment of effect (PGA) in OA-pain after at least 4 weeks [4]. They concluded that diclofenac 150 mg/day is more efficacious than diclofenac 100 mg/day, ibuprofen 1200, and 2400 mg/day, and with similar tolerability in the gastrointestinal tract and kidneys. No cardiovascular side-effects were reported at that time [4].
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2017.03.006. ∗ Corresponding author at: Oslo University Hospital, Department of Pain Management and Research, Pbox 4956 Nydalen, 0424 Oslo, Norway. E-mail address: [email protected]
1. Increased risks from tNSAIDs and COXIBs for serious cardiovascular complications After the rofecoxib story, surprising everybody with a marked increased risk of stroke and myocardial infarction in the long-term preventive studies of colon adenomas and cancers (see [4]), most COXIBs and tNSAIDs with both COX-2 and COX1 specific inhibition (e.g., diclofenac), have had a reputation for exposing patients to unacceptable risk of serious cardiovascular complications, especially stroke and myocardial infarction. Bally et al. published in May 2017 an important, large (446 763 persons) individual patient data-meta-analysis in the British Medical Journal [5]. They conclude that: “All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDs and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.”[5] It is important that they document that increased risk of myocardial infarction occurs in the first week of exposure to a NSAID: “the risk of myocardial infarction with NSAID use increases immediately with exposure” [5]. Short-term uses (8–30 days) at high daily doses of celecoxib >200 mg/day, diclofenac >100 mg/day, ibuprofen >1200 mg/day, or naproxen >750 mg/day) are associated with the highest risk of harm. They could not document further increased risk after the first 30 days [5]. Although the overall risk is small for these rare, but serious, complications in most patients, when other risk factors are present, such as high blood pressure, obesity, and low daily physical activity in an older adult, the absolute risk is not negligible. It is worrisome that these patients are able to buy ibuprofen, naproxen, or diclofenac “over the counter” without a physician’s prescription and without advice about the cardiovascular risks of using NSAIDs.
http://dx.doi.org/10.1016/j.sjpain.2017.05.009 1877-8860/© 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
H. Breivik / Scandinavian Journal of Pain 16 (2017) 148–149
2. Treating pain in elderly patients with osteoarthritis pain All tNSAIDs are ulcerogenic in the gastrointestinal tract, they inhibit platelets, and as the COX-2 inhibitors, they inhibit prostacyclin production by vascular endothelia cells in renal vessels, risking kidney dysfunction and hypertension. In most guidelines for analgesic drug use in geriatric patients, NSAIDs are not recommended except during brief periods, of a few days, when OA-pain is peaking and paracetamol is not relieving severe pain well enough [1,6]. However, it now appears that we have been incorrectly informed: it is not correct that the risk of cardiovascular events would increase only after some time, the risk of myocardial infarction increases immediately [5]. 3. Alternatives to NSAIDs in the elderly with severe osteoarthritis-pain 3.1. Condroitin sulfate? For OA-pain, purified chondroitin sulfate (CS) taken by mouth – 800 mg daily – was recently documented to be as effective as 200 mg celecoxib daily. Chondroitin sulfate is without the adverse effects on kidneys and cardiovascular system from tNSAIDs as well as from COX-2 specific inhibitors [7]. 3.2. Drugs for neuropathic pain? OA-pain is not a purely nociceptive tissue degenerative, nociceptive pain; there are components of neuropathic pain as well. Therefore, the first-line drugs for neuropathic pain are often tried, pregabalin in particular. Drugs that may relieve neuropathic pain conditions, such as pregabalin may be tried with a low starting dose and slow escalation of dose. However, pregabalin is excreted by the kidneys, and if dose adjustment according to age related renal degeneration is not heeded, accumulation and serious side-effects, e.g. cognitive reduction, somnolence, and respiratory depression are bound to occur. 3.3. Opioid analgesic drugs? When paracetamol does not relieve pain in doses up to 1 g × 3 daily and the patient already has cardiovascular comorbidity so that the increased risk of myocardial infarction should an NSAID be added, adding an opioid analgesic is appropriate. The risk for opioid abuse is less in elderly patients, but elderly patients may be even more sensitive to all other adverse effects of opioids. Opioid-induced gastrointestinal dysfunction with obstinate constipation is frequent, but can be prevented or treated effectively with naloxegol or another peripherally acting opioid-antagonists (PAMORA) [8]. Opioid-induced dysfunction of endocrine organs with loss of testosterone-production contribute to fatigue, loss of libido and sexual functions. These can be problematic even for elderly patients. If by mistake, a sedative anxiolytic or a hypnotic drug is added to an opioid (and a gabapentinoid), risk of respiratory depression increases significantly. Upper-airway obstruction causing periods of sleep apnea is common in elderly patients, and is severely aggravated by opioids: life-threatening respiratory dysfunctions is a real risk.
149
4. The difficult balancing act of geriatric pain treatment continues. . . Diclofenac up to 100 mg/day, ibuprofen up to 1200 mg/day, and naproxen up to 750 mg/day are about equally effective as OA analgesics, and they will continue to be among the most used of the traditional NSAIDs [9]. Their gastrointestinal and cardiovascular side effects appear to be similar but more frequent and more severe in elderly patients. In our geriatric patients suffering from pain we must always consider co-morbidities in cardiovascular, renal, endocrine, and respiratory organ systems; in such comorbidities with accompanying polypharmacy, the tolerability and safety of all NSAIDs are significantly decreased. Paracetamol in doses up to 1 g three times daily for patients above 50 kg body weight can give meaningful pain relief without the gastrointestinal and renal side effects of NSAIDs. Adding a low dose of diclofenac 75 mg daily or ibuprofen 800 mg daily to paracetamol 1 g 2–3 times a day, may cause additive analgesic effects by these non-opioid analgesic drugs with different mechanisms of effects. However, when the dilemma of adding an opioid arises, continuing at least the paracetamol may reduce the opioid-dose needed. This can reduce the opioid- dose-related adverse effects on gastrointestinal and respiratory organ systems by adding, for instance, buprenorphine low dos transdermal application of 5–10 micorg/h [10]. Conflict of interest None declared. References [1] Mäntyselka P. Balancing act with geriatric pain treatment. Pain 2008;138:1–2. [2] Conaghan PG, Peloso PM, Everett SV, Rajagopalan S, Black CM, Mavros P, Arden NK, Phillips CJ, Rannou F, van de Laar MA, Moore RA, Taylor SD. Inadequate pain relief and large functional loss among patients with knee osteoarthritis: evidence from a prospective multinational longitudinal study of osteoarthritis real-world therapies. Rheumatology (Oxford, England) 2015;54:270–7. [3] Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med 2015;162:46–54. [4] Guyot P, Pandh S, Nixonc RM, Iqbal A, Chaves RL, Moore RA. Efficacy and safety of diclofenac in osteoarthritis: results of a network meta-analysis of unpublished legacy studies. Scand J Pain 2017;16 [in this issue]. [5] Bally M, Dendukuri N, Rich B, Nadeau L, Helin-Salmivaara A, Garbe E, Brophy JM. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ 2017;357:j1909. [6] Carrington Reid M, Eccleston C, Pillemer K. Management of chronic pain in older adults. BMJ 2015;350:h532. [7] Reginster J-Y, Dudler J, Blicharski T, Pavelka K. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT). Ann Rheum Dis 2017;0:1–7. [8] Drewes AM, Munkholm P, Simrén M, Breivik H, Kongsgaard UE, Hatlebakk JG, Agreus L, Friedrichsen M. Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction—recommendations of the Nordic Working Group. Scand J Pain 2016;11:111–22. [9] van Walsem A, Pandhi S, Nixon RM, Guyot P, Karabis A, Moore RA. Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis. Arthritis Res Ther 2015;17:66. [10] Breivik H, Tone Marte Ljosaa TM, Stengaard-Pedersen K, Persson J, Aro H, Villumsen J, Tvinnemose D. A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids. Scand J Pain 2010;1:122–41, http://dx.doi.org/10.1016/j.sjpain.2010.05.035.
Contents lists available at ScienceDirect
Scandinavian Journal of Pain journal homepage: www.ScandinavianJournalPain.com
Editorial comment
NSAIDs relieve osteoarthritis (OA) pain, but cardiovascular safety in question even for diclofenac, ibuprofen, naproxen, and celecoxib: what are the alternatives? Harald Breivik a,b,c,∗ a
University of Oslo, Faculty of Medicine, Oslo, Norway Oslo University Hospital, Department of Pain Management and Research, Oslo, Norway c Oslo University Hospital, Department of Anaesthesiology, Oslo, Norway b
Citing the excellent editorial comment by Pekka Mäntyselkä 10 years ago in PAIN on the “Balancing act with geriatric pain treatment”, World Health Organisation predicts that there will be 1.2 billion people above 60 years by 2025, 2 billion by 2050, and in the developed world the very old, aged 80+, is the fastest growing population group. Persistent pain, due to degenerative diseases, osteoarthritis (OA) in particular, becomes more prevalent as a person ages [1]. Comorbidities and polypharmacies increasingly pose dilemmas with increasing risks of interactions and serious side effects. Pain and dysfunction from OA are poorly relieved [2], but NSAIDs (traditional tNSAIDs and COX-2 specific inhibitors – COXIBs) are still recommended as cornerstones in the pharmacological treatment of OA [3]. In this issue of the Scandinavian Journal of Pain Patricia Guyot and her co-workers with senior author Andrew Moore, publish an interesting network meta-analysis of diclofenac, ibuprofen, naproxen, indomethacine, and piroxicam for osteoarthritis pain [4]. They analyzed data from 29 previously unpublished randomized, controlled (double-blind) trials (RCTs) from the time before the specific COX2-inhibitors appeared and before cardiovascular risks of traditional NSAIDs and the COXIBs were recognized. A network meta-analysis is possible when one drug is compare with placebo and another active drug, and one of these drugs is compare with a third drug in another RCT, and so on, and so on. In a Bayesian network meta-analysis, they compared efficacy and safety of several tNSAIDs [4]. They used changes in VAS-intensity of pain and patients’ global assessment of effect (PGA) in OA-pain after at least 4 weeks [4]. They concluded that diclofenac 150 mg/day is more efficacious than diclofenac 100 mg/day, ibuprofen 1200, and 2400 mg/day, and with similar tolerability in the gastrointestinal tract and kidneys. No cardiovascular side-effects were reported at that time [4].
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2017.03.006. ∗ Corresponding author at: Oslo University Hospital, Department of Pain Management and Research, Pbox 4956 Nydalen, 0424 Oslo, Norway. E-mail address: [email protected]
1. Increased risks from tNSAIDs and COXIBs for serious cardiovascular complications After the rofecoxib story, surprising everybody with a marked increased risk of stroke and myocardial infarction in the long-term preventive studies of colon adenomas and cancers (see [4]), most COXIBs and tNSAIDs with both COX-2 and COX1 specific inhibition (e.g., diclofenac), have had a reputation for exposing patients to unacceptable risk of serious cardiovascular complications, especially stroke and myocardial infarction. Bally et al. published in May 2017 an important, large (446 763 persons) individual patient data-meta-analysis in the British Medical Journal [5]. They conclude that: “All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDs and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.”[5] It is important that they document that increased risk of myocardial infarction occurs in the first week of exposure to a NSAID: “the risk of myocardial infarction with NSAID use increases immediately with exposure” [5]. Short-term uses (8–30 days) at high daily doses of celecoxib >200 mg/day, diclofenac >100 mg/day, ibuprofen >1200 mg/day, or naproxen >750 mg/day) are associated with the highest risk of harm. They could not document further increased risk after the first 30 days [5]. Although the overall risk is small for these rare, but serious, complications in most patients, when other risk factors are present, such as high blood pressure, obesity, and low daily physical activity in an older adult, the absolute risk is not negligible. It is worrisome that these patients are able to buy ibuprofen, naproxen, or diclofenac “over the counter” without a physician’s prescription and without advice about the cardiovascular risks of using NSAIDs.
http://dx.doi.org/10.1016/j.sjpain.2017.05.009 1877-8860/© 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
H. Breivik / Scandinavian Journal of Pain 16 (2017) 148–149
2. Treating pain in elderly patients with osteoarthritis pain All tNSAIDs are ulcerogenic in the gastrointestinal tract, they inhibit platelets, and as the COX-2 inhibitors, they inhibit prostacyclin production by vascular endothelia cells in renal vessels, risking kidney dysfunction and hypertension. In most guidelines for analgesic drug use in geriatric patients, NSAIDs are not recommended except during brief periods, of a few days, when OA-pain is peaking and paracetamol is not relieving severe pain well enough [1,6]. However, it now appears that we have been incorrectly informed: it is not correct that the risk of cardiovascular events would increase only after some time, the risk of myocardial infarction increases immediately [5]. 3. Alternatives to NSAIDs in the elderly with severe osteoarthritis-pain 3.1. Condroitin sulfate? For OA-pain, purified chondroitin sulfate (CS) taken by mouth – 800 mg daily – was recently documented to be as effective as 200 mg celecoxib daily. Chondroitin sulfate is without the adverse effects on kidneys and cardiovascular system from tNSAIDs as well as from COX-2 specific inhibitors [7]. 3.2. Drugs for neuropathic pain? OA-pain is not a purely nociceptive tissue degenerative, nociceptive pain; there are components of neuropathic pain as well. Therefore, the first-line drugs for neuropathic pain are often tried, pregabalin in particular. Drugs that may relieve neuropathic pain conditions, such as pregabalin may be tried with a low starting dose and slow escalation of dose. However, pregabalin is excreted by the kidneys, and if dose adjustment according to age related renal degeneration is not heeded, accumulation and serious side-effects, e.g. cognitive reduction, somnolence, and respiratory depression are bound to occur. 3.3. Opioid analgesic drugs? When paracetamol does not relieve pain in doses up to 1 g × 3 daily and the patient already has cardiovascular comorbidity so that the increased risk of myocardial infarction should an NSAID be added, adding an opioid analgesic is appropriate. The risk for opioid abuse is less in elderly patients, but elderly patients may be even more sensitive to all other adverse effects of opioids. Opioid-induced gastrointestinal dysfunction with obstinate constipation is frequent, but can be prevented or treated effectively with naloxegol or another peripherally acting opioid-antagonists (PAMORA) [8]. Opioid-induced dysfunction of endocrine organs with loss of testosterone-production contribute to fatigue, loss of libido and sexual functions. These can be problematic even for elderly patients. If by mistake, a sedative anxiolytic or a hypnotic drug is added to an opioid (and a gabapentinoid), risk of respiratory depression increases significantly. Upper-airway obstruction causing periods of sleep apnea is common in elderly patients, and is severely aggravated by opioids: life-threatening respiratory dysfunctions is a real risk.
149
4. The difficult balancing act of geriatric pain treatment continues. . . Diclofenac up to 100 mg/day, ibuprofen up to 1200 mg/day, and naproxen up to 750 mg/day are about equally effective as OA analgesics, and they will continue to be among the most used of the traditional NSAIDs [9]. Their gastrointestinal and cardiovascular side effects appear to be similar but more frequent and more severe in elderly patients. In our geriatric patients suffering from pain we must always consider co-morbidities in cardiovascular, renal, endocrine, and respiratory organ systems; in such comorbidities with accompanying polypharmacy, the tolerability and safety of all NSAIDs are significantly decreased. Paracetamol in doses up to 1 g three times daily for patients above 50 kg body weight can give meaningful pain relief without the gastrointestinal and renal side effects of NSAIDs. Adding a low dose of diclofenac 75 mg daily or ibuprofen 800 mg daily to paracetamol 1 g 2–3 times a day, may cause additive analgesic effects by these non-opioid analgesic drugs with different mechanisms of effects. However, when the dilemma of adding an opioid arises, continuing at least the paracetamol may reduce the opioid-dose needed. This can reduce the opioid- dose-related adverse effects on gastrointestinal and respiratory organ systems by adding, for instance, buprenorphine low dos transdermal application of 5–10 micorg/h [10]. Conflict of interest None declared. References [1] Mäntyselka P. Balancing act with geriatric pain treatment. Pain 2008;138:1–2. [2] Conaghan PG, Peloso PM, Everett SV, Rajagopalan S, Black CM, Mavros P, Arden NK, Phillips CJ, Rannou F, van de Laar MA, Moore RA, Taylor SD. Inadequate pain relief and large functional loss among patients with knee osteoarthritis: evidence from a prospective multinational longitudinal study of osteoarthritis real-world therapies. Rheumatology (Oxford, England) 2015;54:270–7. [3] Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med 2015;162:46–54. [4] Guyot P, Pandh S, Nixonc RM, Iqbal A, Chaves RL, Moore RA. Efficacy and safety of diclofenac in osteoarthritis: results of a network meta-analysis of unpublished legacy studies. Scand J Pain 2017;16 [in this issue]. [5] Bally M, Dendukuri N, Rich B, Nadeau L, Helin-Salmivaara A, Garbe E, Brophy JM. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ 2017;357:j1909. [6] Carrington Reid M, Eccleston C, Pillemer K. Management of chronic pain in older adults. BMJ 2015;350:h532. [7] Reginster J-Y, Dudler J, Blicharski T, Pavelka K. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT). Ann Rheum Dis 2017;0:1–7. [8] Drewes AM, Munkholm P, Simrén M, Breivik H, Kongsgaard UE, Hatlebakk JG, Agreus L, Friedrichsen M. Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction—recommendations of the Nordic Working Group. Scand J Pain 2016;11:111–22. [9] van Walsem A, Pandhi S, Nixon RM, Guyot P, Karabis A, Moore RA. Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis. Arthritis Res Ther 2015;17:66. [10] Breivik H, Tone Marte Ljosaa TM, Stengaard-Pedersen K, Persson J, Aro H, Villumsen J, Tvinnemose D. A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids. Scand J Pain 2010;1:122–41, http://dx.doi.org/10.1016/j.sjpain.2010.05.035.