Opioid dependence among people with haemophilia in a low-resource tropical setting: prevalence and risk factors in northern Nigeria

Open access


Background: In tropical countries such as Nigeria, where factor VIII (FVIII) is scarce, severe pain due to musculoskeletal bleeding complications, leading to frequent opioid prescription, is not uncommon in poorly managed people with haemophilia (PWH). The relationship between opioid use and dependence is intensively studied in other painful diseases, such as cancer and rheumatoid arthritis, but surprisingly little is known about opioid dependence in haemophilia. We hypothesise that the risk of opioid dependence among PWH in tropical countries like Nigeria is multi-factorial, encompassing demographic (age), clinical (haemophilia severity and chronic arthropathy) and biological (ABO blood groups and haemoglobin (Hb) phenotypes) factors that may directly or indirectly increase incidence of bleeding and/or pain.

Aims: To determine the prevalence of opioid dependence and relative risks (RR) associated with age, haemophilia severity, chronic arthropathy, ABO blood groups and Hb phenotypes, and to elucidate the pathophysiological roles of each risk factor in the development of opioid dependence among haemophilia-A patients in five hospitals in northern Nigeria.

Methodology: A retrospective review of the medical records of 88 PWH seen between 1996 and 2012 was used to collate data on age, sex, haemophilia severity, painful chronic haemophilic arthropathy, ABO blood group, haemoglobin phenotypes, presence or absence of opioid dependence, and the types of opioids on which the patients were dependent. The prevalence of opioid dependence among the cohort was expressed as a percentage. The frequency of each putative risk factor for opioid dependence in patients with and without opioid dependence were compared using Fisher’s exact test; RR associated with each risk factor was determined by regression analysis. P<0.05 was taken as significant.

Results: Of the 88 PWH studied,15 (17%) were shown to be opioid-dependent. Compared with PWH who were not opioid-dependent, this group had higher frequencies of severe haemophilia (86.7% vs. 49.3%: RR= 5.2, p=0.02), survival to adulthood (73.3% vs. 12.3%: RR= 9.5, p=0.0001), chronic arthropathy in one or more joints (86.7% vs. 21.9%: RR= 13.2, p=0.0004), blood group-O (80% vs. 49.3%: RR= 3.3, p=0.04), and HbAA phenotype (86.7% vs. 54.8%: RR= 4.3, p=0.04).

Conclusion: Prevalence of opioid dependence among PWH treated at five hospitals in northern Nigeria was 17% during the study period. Significant risk factors were directly or indirectly associated with increased rates of bleeding and/or pain, which can only be prevented or treated through optimal application of FVIII. There is a need for the Nigerian government to establish standard haemophilia care centres with adequate FVIII for optimal prophylaxis and treatment in order to minimise painful complications, thereby helping to prevent undue opioid use and dependence.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Tantawy AAG. Molecular genetics of hemophilia A: clinical perspectives. Egypt J Med Hum Genet 2010; 11: 105–14. doi:10.1016/j.ejmhg.2010.10.005.

  • 2. Ibrahim UA Ahmed SG. Pathophysiology of bleeding diathesis in haemophilia-A: a sequential and critical appraisal of non-FVIII related haemostatic dysfunctions and their therapeutic implications. Egypt J Med Hum Genet 2018; 19: 285–95. doi:10.1016/j.ejmhg.2018.01.003.

  • 3. Brinkmann T Kähnert H Prohaska W et al. Synthesis of tissue factor pathway inhibitor in human synovial cells and chondrocytes makes joints the predilected site of bleeding in haemophiliacs. Eur J Clin Chem Clin Biochem 1994; 32 :313–7.

  • 4. Nieuwenhuizen L Schutgens RE van Asbeck BS et al. Identification and expression of iron regulators in human synovium: evidence for upregulation in haemophilic arthropathy compared to rheumatoid arthritis osteoarthritis and healthy controls. Haemophilia 2013; 19: e218–e227. doi:10.1111/hae.12208.

  • 5. Drake TA Morrissey JH Edgington TS. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol 1989; 134(5): 1087–97.

  • 6. Chu AJ. Tissue factor blood coagulation and beyond: an overview. Int J Inflam 2011; 367284. doi: 10.4061/2011/367284.

  • 7. Qasim Z Naseem L Asif N Hassan K. Haemophilia: pattern of clinical presentation and disease severity. Int J Pathol 2013; 11: 58–63.

  • 8. Rodriguez-Merchan EC. Musculoskeletal complications of hemophilia. HSS J 2010; 6: 37–42. doi: 10.1007/s11420-009-9140-9.

  • 9. Roussel NA. Gaining insight into the complexity of pain in patients with haemophilia: state-of-the-art review on pain processing. Haemophilia 2018; 24: 3–8. doi: 10.1111/hae.13509.

  • 10. Ghosh K Ghosh K. Management of haemophilia in developing countries: challenges and options. Indian J Hematol Blood Transfus 2016;32: 347–55. doi: 10.1007/s12288-015-0562-x.

  • 11. Ahmed SG Kagu MB Ibrahim UA. Pattern of blood products transfusions and reactions among multi-transfused haemophiliacs in Nigeria: implications on haemophilia care in low resource tropical settings. Sudan Med J 2018; 54: 29–38. doi: 10.12816/0046389.

  • 12. Auerswald G Dolan G Duffy A et al. Pain and pain management in haemophilia. Blood Coagul Fibrinolysis 2016; 27: 845–54. doi: 10.1097/MBC.0000000000000571.

  • 13. Volkow ND McLellan AT. Opioid abuse in chronic pain – misconceptions and mitigation strategies. N Engl J Med 2016; 374: 1253–63. doi: 10.1056/NEJMra1507771.

  • 14. Witkop M Lambing A Divine G et al. A national study of pain in the bleeding disorders community: a description of haemophilia pain. Haemophilia 2012; 18(3): e115–9. doi: 10.1111/j.1365-2516.2011.02709.x.

  • 15. Forsyth AL Gregory M Nugent D et al. Haemophilia Experiences Results and Opportunities (HERO) study: survey methodology and population demographics. Haemophilia 2014 20(1): 44–51. doi: 10.1111/hae.12239.

  • 16. Forsyth AL Witkop M Lambing A et al. Associations of quality of life pain and self-reported arthritis with age employment bleed rate and utilization of hemophilia center and health care provider services: results in adults in the HERO study. Patient Prefer Adherence 2015; 9: 1549–60. doi: 10.2147/PPA.S87659.

  • 17. Humphries TJ Kessler CM. Managing chronic pain in adults with haemophilia: current status and call to action. Haemophilia 2015; 21:41–51. doi:10.1111/hae.12526.

  • 18. Varni JW Gilberta A. Self-regulation of chronic arthritic pain and long-term analgesic dependence in a haemophiliac. Rheumatol Rehabil 1982; 21: 171–4. doi: 10.1093/rheumatology/21.3.171.

  • 19. Laffan M Manning R. Investigation of haemostasis. In: Lewis SM Bain BJ Bates I eds. Practical Haematology 10th edn. London: Churchill Livingstone; 2006: 379–440.

  • 20. Rowley M Milkins C. Laboratory aspects of blood transfusion. In: Lewis SM Bain BJ Bates I eds. Practical Haematology 10th edn. London: Churchill Livingstone; 2006: 523–54.

  • 21. Wild B Bain BJ. Investigation of abnormal haemoglobins and thalassaemia. In: Lewis SM Bain BJ Bates I eds. Practical Haematology 10th edn. London: Churchill Livingstone; 2006: 271–310.

  • 22. Alhaosawi MM. Guidelines of management of musculoskeletal complications of hemophilia. J Appl Hematol 2014; 5: 75–85. doi: 10.4103/1658-5127.141988.

  • 23. Arnold WD Hilgartner MW. Hemophilic arthropathy. Current concepts of pathogenesis and management. J Bone Joint Surg Am 1977; 59(3): 287–305.

  • 24. Gorfinkel L Voon P Wood E Klimas J. Diagnosing opioid addiction in people with chronic pain BMJ 2018; 362:k3949. doi: 10.1136/bmj.k3949.

  • 25. Mistry CJ Bawor M Desai D et al. Genetics of opioid dependence: a review of the genetic contribution to opioid dependence. Curr Psychiatry Rev 2014; 10: 156–67.

  • 26. Ibrahim UA Ahmed SG. Determinants and modifiers of bleeding phenotypes in haemophilia-A: general and tropical perspectives. Egypt J Med Hum Genet 2018; 19: 171–8. doi: 10.1016/j.ejmhg.2017.10.004.

  • 27. Sharathkumar A Lillicrap D Blanchette VS et al. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A. J Thromb Haemost 2003; 1: 1228–36.

  • 28. Mathews V Nair SC David S et al. Management of hemophilia in patients with inhibitors: the perspective from developing countries. Semin Thromb Hemost 2009; 35: 820–6. doi: 10.1055/s-00291245115.

  • 29. Stonebraker JS Bolton-Maggs PH et al. A study of variations in the reported haemophilia A prevalence around the world. Haemophilia 2010; 16: 20–32. doi: 10.1111/j.1365-2516.2009.02127.x.

  • 30. Joint Formulary Committee. Drugs acting on the nervous system. British National Formulary 70. London: BMJ Group and Pharmaceutical Press; 2015: 262–437.

  • 31. Kircher S Zacny J Apfelbaum SM et al. Understanding and treating opioid addiction in a patient with cancer pain. J Pain 2011; 12: 1025–31. doi: 10.1016/j.jpain.2011.07.006.

  • 32. Zamora-Legoff JA Achenbach SJ Crowson CS et al. Opioid use in patients with rheumatoid arthritis 2005-2014: a population-based comparative study. Clin Rheumatol 2016; 35: 1137–44. doi: 10.1007/s10067-016-3239-4.

  • 33. Ahmed SG Ibrahim UA. The prevalence of therapeutic opiate dependence among patients with sickle cell disease in Maiduguri north-east Nigeria. Nig J Pharm 2001; 32: 56–9.

  • 34. Ahmed SG Ibrahim UA. Disease severity indices in sickle cell anaemia patients with therapeutic opiate dependence in Nigeria. Hamdard Med 2008; 51: 79–83.

  • 35. Nossent AY van Marion V van Tilburg NH et al. von Willebrand factor and its propeptide: the influence of secretion and clearance on protein levels and the risk of venous thrombosis. J Thromb Haemost 2006; 4: 2556–62.

  • 36. Gallinaro L Cattini MG Sztukowska M et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111: 3540–5. doi: 10.1182/blood-2007-11-122945.

  • 37. Jenkins PV O’Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all? Transfusion 2006; 46: 1836–44.

  • 38. Federici AB. The factor VIII/von Willebrand factor complex: basic and clinical issues. Haematologica 2003; 88: EREP02.

  • 39. Song J Chen F Campos M et al. Quantitative influence of ABO blood groups on factor VIII and its ratio to von Willebrand factor novel observations from an ARIC study of 11673 subjects. PLoS One 2015; 10: e0132626. doi: 10.1371/journal.pone.0132626.

  • 40. Reininger AJ Heijnen HF Schumann H et al. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress. Blood 2006; 107: 3537–45. doi: 10.1182/blood-2005-02-0618.

  • 41. Dentali F Sironi AP Ageno W et al. Non-O blood type is the commonest genetic risk factor for VTE: results from a metaanalysis of the literature. Semin Thromb Hemost 2012; 38: 535–48. doi: 10.1055/s-0032-1315758.

  • 42. Reddy VM Daniel M Bright E et al. Is there an association between blood group O and epistaxis? J Laryngol Otol 2008; 122: 366–8.

  • 43. Welsby IJ Jones R Pylman J et al. ABO blood group and bleeding after coronary artery bypass graft surgery. Blood Coagul Fibrinolysis 2007; 18: 781–5.

  • 44. Franchini M Crestani S Frattini F et al. Relationship between ABO blood group and bleeding complications in orally anticoagulated patients. J Thromb Haemost 2012; 10: 1688– 91. doi: 10.1111/j.1538-7836.2012.04785.x.

  • 45. Ahmed SG Kagu MB Ibrahim UA. Correlation between ABO blood groups and spontaneous bleeding rates in severe haemophilia-A. Sudan Med J 2017; 53: 162–9. Available from http://www.smj.eg.net/journals/pdf/825.pdf (accessed 4 April 2019).

  • 46. Hazendonk HC Lock J Mathôt RA et al. Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications. J Thromb Haemost 2016; 14: 468–78. doi:10.1111/jth.13242.

  • 47. Fleming AF Storey J Molineaux L et al. Abnormal haemoglobins in the Sudan savanna of Nigeria: I. Prevalence of haemoglobins and relationships between sickle cell trait malaria and survival. Ann Trop Med Parasitol 1979; 73: 161–72.

  • 48. Elguero E Délicat-Loembet LM Rougeron V et al. Malaria continues to select for sickle cell trait in Central Africa. Proc Natl Acad Sci USA 2015; 112: 7051–4. doi: 10.1073/pnas.1505665112.

  • 49. PO Olatunji. Malaria and the sickle gene: polymorphism balance in favour of eradication Ann Health Res 2018; 4: 88–96. doi: 10.30442/ahr.0402-1-12.

  • 50. Gong L Parikh S Rosenthal PJ Greenhouse B. Biochemical and immunological mechanisms by which sickle cell trait protects against malaria. Malar J 2013; 12: 317. doi: 10.1186/1475-2875-12-317.

  • 51. Westerman MP Green D Gilman-Sachs A et al. Coagulation changes in individuals with sickle cell trait. Am J Hematol 2002; 69: 89–94. doi: 10.1002/ajh.10021.

  • 52. Tait JF Gibson D. Measurement of membrane phospholipid asymmetry in normal and sickle cell erythrocytes by means of annexin V binding. J Lab Clin Med 1994; 123: 741–8.

  • 53. Westerman MP Cole ER Wu K. The effect of spicules obtained from sickle red cells on clotting activity. Br J Haematol 1984; 56: 557–62.

  • 54. Austin H Key NS Benson JM et al. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007; 110: 908–12. doi: 10.1182/blood-2006-11-057604.

  • 55. Ahmed SG Ibrahim UA Kagu MB Abjah UA. Does sickle cell trait reduce the frequency of spontaneous bleeds in severe haemophilia? J Haem Pract 2016; 3: 1–5. doi: 10.17225/jhp00083.

  • 56. Dhiman P Chaudhary R Sudha K. Sickle cell-ß thalassemia with concomitant hemophilia A: a rare presentation. Blood Res 2015; 50: 264–67. doi: 10.5045/br.2015.50.4.264.

  • 57. Qasim Z. Pattern of haemarthrosis in haemophilia. J Rawalpindi Med College 2013; 17: 204–6. Available from https://www.journalrmc.com/volumes/1395217838.pdf (accessed 4 April 2019).

  • 58. Melchiorre D Manetti M Matucci-Cerinic M. Pathophysiology of hemophilic arthropathy. J Clin Med 2017; 6: 63. doi: 10.3390/jcm6070063.

  • 59. Chang CY Li TY Cheng SN et al. Prevalence and severity by age and other clinical correlates of haemophilic arthropathy of the elbow knee and ankle among Taiwanese patients with haemophilia. Haemophilia 2017; 23: 284–91. doi: 10.1111/hae.13117.

  • 60. Rodriguez-Merchan EC. Prevention of the musculoskeletal complications of hemophilia. Adv Prev Med 2012: 201271. doi: 10.1155/2012/201271.

Journal information
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 121 121 23
PDF Downloads 99 99 6