LETTERS TO THE EDITORS
e487
Pain management strategies in adults with haemophilia: a retrospective study X . W A N G , * M . Y A N G † and S . J A C K S O N ‡ *Department of Pathology and Medical Laboratory Science, Faculty of Medicine University of British Columbia; †British Columbia Provincial Bleeding Disorders Program – Adult Division; and ‡Division of Hematology, Department of Medicine University of British Columbia, Vancouver, BC, Canada
Individuals with haemophilia experience acute and chronic pain which, on an average day, can reach an intensity of 5/10 [1]. Although options exist for managing acute and chronic pain, many patients with haemophilia do not achieve good control of pain. Several studies have looked at the impact of pain in severe haemophilia [2,3]; however, the management of pain in all severities of the haemophilia population have not been investigated thoroughly, especially in Canada where factor concentrates are widely available. The purpose of this study was to describe the past pain management techniques, hereafter called pain strategies, in a large haemophilia population. Particular areas of interest were the use of opiates, non-steroidal anti-inflammatory agents (NSAIDs; including celecoxib), and use of marijuana for pain. All males with a diagnosis of haemophilia A or B from a single Adult Haemophilia Centre who had an active record between 2004 (when the clinic moved to its current location) and May 2012 had their chart reviewed. Pain management strategies used during those years were categorized by type, dosage, frequency and targeted site(s). A total of 210 subjects were included, 75% with haemophilia A and 25% with haemophilia B. The prevalence of severe, moderate and mild haemophilia was 35% (n = 73), 23% (n = 49) and 42% (n = 88) respectively. The mean age was 41 years and the median 38 years (range = 17–76). Most subjects (60%, n = 126) had used a pain strategy, during the 8 year period, according to the written records. Of those using a pain strategy, 70 subjects (55%) had used acetaminophen and 30 subjects (24%) used acetaminophen in combination with codeine. NSAIDs were used in 69 subjects (55%), opiates in 32 subjects
(25%) and 53 subjects (42%) used some other form of pain strategy. Most subjects (94/126) were using more than one form of pain strategy. Opiates were used either alone or in conjunction with other pain analgesics in only 15% (32/210) of the overall population. The most commonly used agents were morphine (41%, 13/32), hydromorphine (28%, 9/32), codeine (19%, 6/32) and oxycodone (16%, 5/32). When opiate use was evaluated by haemophilia severity, the prevalence was as follows; 22% (16/73) of severe, 14% (7/49) of moderate and 10% (9/88) of mild subjects had reported use of opiates. A similar trend by haemophilia severity was observed with the other pain strategies with a variation of 5%. This may have been influenced by a lack of older individuals in the severe haemophilia group (Fig. 1); thus opiate usage due to age-related factors (i.e. arthritis) is not accounted for; whereas in the milder subjects, a more representative population of older individuals survives (Fig. 1). Many patients may be reluctant to use opiates as analgesics for fear of drug dependency [4], which could explain why severe subjects, who have more potential reasons for severe pain, may choose not to use opiates. Controversies surrounding opiate usage make it difficult or unappealing for practitioners to prescribe; however, contrary to popular beliefs, the risk of dependence of opiate usage to treat chronic pain is low [5]. Celecoxib, a COX2 specific NSAID, was used in 14% (29/210) subjects as a pain strategy. Twenty-six percent of individuals with severe haemophilia used 35 Severe (n = 73) 30
Mild (n = 88)
Correspondence: Shannon Jackson, Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. c/o British Columbia Provincial Bleeding Disorders Program – Adult Division, 1081 Burrard Street, Comox Building, Room 217, Vancouver, British Columbia V6Z 1Y6, Canada Tel.: 604-806-8855; fax: 604-806-8784; e-mail: [email protected] Accepted after revision 11 May 2015 DOI: 10.1111/hae.12753 © 2015 John Wiley & Sons Ltd
Frequency
25 20 15 10 5 0 0–20
21–30 31–40 41–50 51–60 61–70 71–80 81–90 Age
>90
Fig. 1. Comparison of age distribution between severe and mild subjects.
Haemophilia (2015), 21, e479--e525
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LETTERS TO THE EDITORS
celecoxib in contrast to only four percent of those with mild haemophilia (Fig. 2). Traditional NSAIDs were used at a higher frequency than celecoxib, with 19% (40/210) noted to have used NSAIDs for pain, including 10 subjects with severe haemophilia. However, in the severe haemophilia population, celecoxib was used more frequently than traditional NSAID’s (Fig. 3). We were very interested in the use of celecoxib because of its theoretical increased safety profile in bleeding disorders and previously reported use in the haemophilia population [6]. Most practitioners in the setting of severe haemophilia would avoid regular use of traditional NSAIDs due to risks of GI and other mucocutaneous bleeding, although individuals on intense prophylaxis may be an exception. Having an alternative anti-inflammatory agent in the form of
Using celebrex Not using celebrex
Severity
Mild
3
Moderate
4%
78
7
14%
42
Severe
19
0
26%
54
10
20
30
40
50
60
70
80
90
Number of subjects
Fig. 2. Use of celecoxib (Celebrex) as a pain strategy according to hemophilia severity.
Using celebrex Using traditional NSAIDs
Severity
Mild
3
Moderate
86%
19
7
61%
11
Severe
19
0
5
10
10
15
20
25
34%
30
35
a COX2 inhibitor to target inflammatory and arthritic pain without the inherent platelet dysfunction is an attractive option, and one that 26% of the severe population has used or is using. Through the medical record we did not have the ability to determine if either celecoxib or the traditional NSAIDs were associated with bleeding complications. Use of marijuana as a pain strategy also increases with severity of haemophilia. According to the medical record, marijuana as a pain strategy in the haemophilia population was low at 7% (15/210), however, twelve percent of individuals with severe haemophilia used marijuana for pain in contrast to only four percent of those with mild haemophilia. Due to functional limitations of chronic arthropathy, some haemophilia patients cannot cope well with physical therapy [7] and/or may prefer non-traditional pain strategies. As previously mentioned, individuals with all severities of haemophilia may be reluctant to use opiates; therefore marijuana may be a preferred alternative. Marijuana contains psychoactive compounds such as tetrahydrocannabinol that can relieve pain by acting on cannabinoid receptors in brain and spinal nerves. This allows the individual to perceive the pain differently, thus enabling an alternative means of tolerating pain [8]. Subjects may prefer these non-traditional options (celecoxib and marijuana) over opiates due to concerns about addiction and a perception that opiates are not ideal in this situation (by patients and primary caregivers). In our clinic, the physician does not prescribe opiates and there will also be variability in different family physicians’ comfort level in prescribing opiates. Our methodology did not allow us to explore the prevalence of medically prescribed marijuana in our cohort and likely underestimated the true prevalence of this strategy. We provide additional evidence that the use of pain strategies is common for individuals with haemophilia. By analyzing analgesic prevalence among different severities we have gained awareness of various pain management strategies used by our patients. With this information, assessment tools, treatment protocols and educational activities can now be put in place to identify options for the ~60% of patients who appear to use analgesic treatment in our haemophilia population. Specifically, the use of traditional NSAIDs in 1/5 of this population warrants an effort to promote awareness about the relative risk to benefit ratio.
Acknowledgements
Number of subjects
Fig. 3. Reported use of traditional non-steroidal anti-inflammatory agents (NSAIDs) as a pain strategy according to hemophilia severity.
Haemophilia (2015), 21, e479--e525
X Wang was the recipient of the summer student scholarship from the UBC Bleeding Disorders Collaboratory, which was supported in part by an unrestricted grant from Bayer Inc.
© 2015 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
e489
Author contributions
Disclosures
M Yang and S Jackson designed the study. X Wang, M Yang and S Jackson performed the research and data analysis and wrote the manuscript.
The authors stated that they had no interest which might be perceived as posing a conflict or bias.
References 1 Witkop M, Lambing A, Kachalsky E, Divine G, Rushlow D, Dinnen J. Assessment of acute and persistent pain management in patients with haemophilia. Haemophilia 2011; 17: 615–9. 2 Van Genderen FR, Fischer K, Heijnen L et al. Pain and functional limitations in patients with severe haemophilia. Haemophilia 2006; 12: 147–53. 3 Moulin DE, Clark AJ, Speechley M, MorleyForster PK. Chronic pain in Canada–preva-
lence, treatment, impact and the role of opioid analgesia. Pain Res Manag 2002; 7: 179–84. 4 Marcus DA. Chronic Pain: A Primary Care Guide to Practical Management. Totowa, NJ: Humana Press, 2009. 5 Witkop M, Lambing A, Kachalsky E, Divine G, Rushlow D, Dinnen J. A national study of pain in the bleeding disorders community: a description of haemophilia pain. Haemophilia 2012; 18: 115–9.
6 Frace RD, Urban BJ, Keefe FJ. Long-term use of narcotic analgesics in chronic pain. Soc Sci Med 1984; 19: 1379–82. 7 Battray B, Nugent DJ, Young G. Celecoxib in the treatment of haemophilic synovitis, target joints, and pain in adults and children with haemophilia. Haemophilia 2006; 12: 514–7. 8 Greenwell GT. Medical marijuana use for chronic pain: risks and benefits. J Pain Palliat Care Pharmacother 2012; 26: 68– 9.
Response to Gringeri et al.: ‘recombinant full-length factor VIII (FVIII) and extended half-life FVIII products in prophylaxis – new insight provided by pharmacokinetic modelling’ A . D . S H A P I R O * and S . L I † *Department of Hematology, Indiana Hemophilia and Thrombosis Center, Indianapolis, IN; and †Biogen, Cambridge, MA, USA
In the recent article by Gringeri et al. [1] entitled ‘Recombinant full-length factor VIII (FVIII) and extended half-life FVIII products in prophylaxis – new insight provided by pharmacokinetic modelling’, the authors present data from simulations based on independent population pharmacokinetic models for rAHF-PFM [2], a third-generation standard half-life recombinant FVIII (rFVIII) therapy, and rFVIII Fc fusion protein (rFVIIIFc) [3], a prolonged half-life rFVIII. These simulations predict that dosing patients with an extended half-life FVIII product at 1.5-fold longer intervals compared with a standard half-life FVIII product (i.e. every 72 h vs. every 48 h) may lead to more time (i.e. 0.05 h longer) with lower FVIII levels (e.g.
e487
Pain management strategies in adults with haemophilia: a retrospective study X . W A N G , * M . Y A N G † and S . J A C K S O N ‡ *Department of Pathology and Medical Laboratory Science, Faculty of Medicine University of British Columbia; †British Columbia Provincial Bleeding Disorders Program – Adult Division; and ‡Division of Hematology, Department of Medicine University of British Columbia, Vancouver, BC, Canada
Individuals with haemophilia experience acute and chronic pain which, on an average day, can reach an intensity of 5/10 [1]. Although options exist for managing acute and chronic pain, many patients with haemophilia do not achieve good control of pain. Several studies have looked at the impact of pain in severe haemophilia [2,3]; however, the management of pain in all severities of the haemophilia population have not been investigated thoroughly, especially in Canada where factor concentrates are widely available. The purpose of this study was to describe the past pain management techniques, hereafter called pain strategies, in a large haemophilia population. Particular areas of interest were the use of opiates, non-steroidal anti-inflammatory agents (NSAIDs; including celecoxib), and use of marijuana for pain. All males with a diagnosis of haemophilia A or B from a single Adult Haemophilia Centre who had an active record between 2004 (when the clinic moved to its current location) and May 2012 had their chart reviewed. Pain management strategies used during those years were categorized by type, dosage, frequency and targeted site(s). A total of 210 subjects were included, 75% with haemophilia A and 25% with haemophilia B. The prevalence of severe, moderate and mild haemophilia was 35% (n = 73), 23% (n = 49) and 42% (n = 88) respectively. The mean age was 41 years and the median 38 years (range = 17–76). Most subjects (60%, n = 126) had used a pain strategy, during the 8 year period, according to the written records. Of those using a pain strategy, 70 subjects (55%) had used acetaminophen and 30 subjects (24%) used acetaminophen in combination with codeine. NSAIDs were used in 69 subjects (55%), opiates in 32 subjects
(25%) and 53 subjects (42%) used some other form of pain strategy. Most subjects (94/126) were using more than one form of pain strategy. Opiates were used either alone or in conjunction with other pain analgesics in only 15% (32/210) of the overall population. The most commonly used agents were morphine (41%, 13/32), hydromorphine (28%, 9/32), codeine (19%, 6/32) and oxycodone (16%, 5/32). When opiate use was evaluated by haemophilia severity, the prevalence was as follows; 22% (16/73) of severe, 14% (7/49) of moderate and 10% (9/88) of mild subjects had reported use of opiates. A similar trend by haemophilia severity was observed with the other pain strategies with a variation of 5%. This may have been influenced by a lack of older individuals in the severe haemophilia group (Fig. 1); thus opiate usage due to age-related factors (i.e. arthritis) is not accounted for; whereas in the milder subjects, a more representative population of older individuals survives (Fig. 1). Many patients may be reluctant to use opiates as analgesics for fear of drug dependency [4], which could explain why severe subjects, who have more potential reasons for severe pain, may choose not to use opiates. Controversies surrounding opiate usage make it difficult or unappealing for practitioners to prescribe; however, contrary to popular beliefs, the risk of dependence of opiate usage to treat chronic pain is low [5]. Celecoxib, a COX2 specific NSAID, was used in 14% (29/210) subjects as a pain strategy. Twenty-six percent of individuals with severe haemophilia used 35 Severe (n = 73) 30
Mild (n = 88)
Correspondence: Shannon Jackson, Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. c/o British Columbia Provincial Bleeding Disorders Program – Adult Division, 1081 Burrard Street, Comox Building, Room 217, Vancouver, British Columbia V6Z 1Y6, Canada Tel.: 604-806-8855; fax: 604-806-8784; e-mail: [email protected] Accepted after revision 11 May 2015 DOI: 10.1111/hae.12753 © 2015 John Wiley & Sons Ltd
Frequency
25 20 15 10 5 0 0–20
21–30 31–40 41–50 51–60 61–70 71–80 81–90 Age
>90
Fig. 1. Comparison of age distribution between severe and mild subjects.
Haemophilia (2015), 21, e479--e525
e488
LETTERS TO THE EDITORS
celecoxib in contrast to only four percent of those with mild haemophilia (Fig. 2). Traditional NSAIDs were used at a higher frequency than celecoxib, with 19% (40/210) noted to have used NSAIDs for pain, including 10 subjects with severe haemophilia. However, in the severe haemophilia population, celecoxib was used more frequently than traditional NSAID’s (Fig. 3). We were very interested in the use of celecoxib because of its theoretical increased safety profile in bleeding disorders and previously reported use in the haemophilia population [6]. Most practitioners in the setting of severe haemophilia would avoid regular use of traditional NSAIDs due to risks of GI and other mucocutaneous bleeding, although individuals on intense prophylaxis may be an exception. Having an alternative anti-inflammatory agent in the form of
Using celebrex Not using celebrex
Severity
Mild
3
Moderate
4%
78
7
14%
42
Severe
19
0
26%
54
10
20
30
40
50
60
70
80
90
Number of subjects
Fig. 2. Use of celecoxib (Celebrex) as a pain strategy according to hemophilia severity.
Using celebrex Using traditional NSAIDs
Severity
Mild
3
Moderate
86%
19
7
61%
11
Severe
19
0
5
10
10
15
20
25
34%
30
35
a COX2 inhibitor to target inflammatory and arthritic pain without the inherent platelet dysfunction is an attractive option, and one that 26% of the severe population has used or is using. Through the medical record we did not have the ability to determine if either celecoxib or the traditional NSAIDs were associated with bleeding complications. Use of marijuana as a pain strategy also increases with severity of haemophilia. According to the medical record, marijuana as a pain strategy in the haemophilia population was low at 7% (15/210), however, twelve percent of individuals with severe haemophilia used marijuana for pain in contrast to only four percent of those with mild haemophilia. Due to functional limitations of chronic arthropathy, some haemophilia patients cannot cope well with physical therapy [7] and/or may prefer non-traditional pain strategies. As previously mentioned, individuals with all severities of haemophilia may be reluctant to use opiates; therefore marijuana may be a preferred alternative. Marijuana contains psychoactive compounds such as tetrahydrocannabinol that can relieve pain by acting on cannabinoid receptors in brain and spinal nerves. This allows the individual to perceive the pain differently, thus enabling an alternative means of tolerating pain [8]. Subjects may prefer these non-traditional options (celecoxib and marijuana) over opiates due to concerns about addiction and a perception that opiates are not ideal in this situation (by patients and primary caregivers). In our clinic, the physician does not prescribe opiates and there will also be variability in different family physicians’ comfort level in prescribing opiates. Our methodology did not allow us to explore the prevalence of medically prescribed marijuana in our cohort and likely underestimated the true prevalence of this strategy. We provide additional evidence that the use of pain strategies is common for individuals with haemophilia. By analyzing analgesic prevalence among different severities we have gained awareness of various pain management strategies used by our patients. With this information, assessment tools, treatment protocols and educational activities can now be put in place to identify options for the ~60% of patients who appear to use analgesic treatment in our haemophilia population. Specifically, the use of traditional NSAIDs in 1/5 of this population warrants an effort to promote awareness about the relative risk to benefit ratio.
Acknowledgements
Number of subjects
Fig. 3. Reported use of traditional non-steroidal anti-inflammatory agents (NSAIDs) as a pain strategy according to hemophilia severity.
Haemophilia (2015), 21, e479--e525
X Wang was the recipient of the summer student scholarship from the UBC Bleeding Disorders Collaboratory, which was supported in part by an unrestricted grant from Bayer Inc.
© 2015 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
e489
Author contributions
Disclosures
M Yang and S Jackson designed the study. X Wang, M Yang and S Jackson performed the research and data analysis and wrote the manuscript.
The authors stated that they had no interest which might be perceived as posing a conflict or bias.
References 1 Witkop M, Lambing A, Kachalsky E, Divine G, Rushlow D, Dinnen J. Assessment of acute and persistent pain management in patients with haemophilia. Haemophilia 2011; 17: 615–9. 2 Van Genderen FR, Fischer K, Heijnen L et al. Pain and functional limitations in patients with severe haemophilia. Haemophilia 2006; 12: 147–53. 3 Moulin DE, Clark AJ, Speechley M, MorleyForster PK. Chronic pain in Canada–preva-
lence, treatment, impact and the role of opioid analgesia. Pain Res Manag 2002; 7: 179–84. 4 Marcus DA. Chronic Pain: A Primary Care Guide to Practical Management. Totowa, NJ: Humana Press, 2009. 5 Witkop M, Lambing A, Kachalsky E, Divine G, Rushlow D, Dinnen J. A national study of pain in the bleeding disorders community: a description of haemophilia pain. Haemophilia 2012; 18: 115–9.
6 Frace RD, Urban BJ, Keefe FJ. Long-term use of narcotic analgesics in chronic pain. Soc Sci Med 1984; 19: 1379–82. 7 Battray B, Nugent DJ, Young G. Celecoxib in the treatment of haemophilic synovitis, target joints, and pain in adults and children with haemophilia. Haemophilia 2006; 12: 514–7. 8 Greenwell GT. Medical marijuana use for chronic pain: risks and benefits. J Pain Palliat Care Pharmacother 2012; 26: 68– 9.
Response to Gringeri et al.: ‘recombinant full-length factor VIII (FVIII) and extended half-life FVIII products in prophylaxis – new insight provided by pharmacokinetic modelling’ A . D . S H A P I R O * and S . L I † *Department of Hematology, Indiana Hemophilia and Thrombosis Center, Indianapolis, IN; and †Biogen, Cambridge, MA, USA
In the recent article by Gringeri et al. [1] entitled ‘Recombinant full-length factor VIII (FVIII) and extended half-life FVIII products in prophylaxis – new insight provided by pharmacokinetic modelling’, the authors present data from simulations based on independent population pharmacokinetic models for rAHF-PFM [2], a third-generation standard half-life recombinant FVIII (rFVIII) therapy, and rFVIII Fc fusion protein (rFVIIIFc) [3], a prolonged half-life rFVIII. These simulations predict that dosing patients with an extended half-life FVIII product at 1.5-fold longer intervals compared with a standard half-life FVIII product (i.e. every 72 h vs. every 48 h) may lead to more time (i.e. 0.05 h longer) with lower FVIII levels (e.g.
