Chronification and mixed pain: Pragmatic best-practice approach to novel chronic pain concepts
11 Jan 2023
The Viatris Pain Summit 2022 – which was held at Shangri-La The Fort
on November 9, 2022 – focused on chronic
pain, which affects about one-fifth of the world’s population and is a
significant cause of morbidity and poor health-related quality of life.1
In her opening address, Ms. Ester Tacanay, General manager of Viatris
Philippines described chronic pain as often overlooked and underappreciated.
The company’s medical manager, Dr Christian Yap II, introduced the distinguished speakers: Professor Dr Bart Morlion, PhD, DEAA, EDPM of Katholieke Universiteit Leuven in Belgium and Professor Dr Rainer Freynhagen, DEAA, EDPM of Technische Universität München in Germany, who shared their expertise on some novel clinical concepts in chronic pain.
From Acute to Chronic: Chronification and optimizing chronic pain treatment
“Chronification” refers to the progression of transient pain into persistent pain, due to an imbalance between the amplification and inhibition of pain. Neurobiological changes in chronification include peripheral and central sensitization, which can result in reduced threshold for nociceptor activation, leading to greater pain sensations, or hyperalgesia.1
Professor Morlion stressed that chronic pain is more about sensitivity than injury. He also pointed out that genetic, environmental, and biopsychosocial factors can positively or negatively impact the risk, degree, and time-course of chronification.1
To optimize the treatment of chronic pain, Prof Morlion advocated for the early management of acute pain, multimodal pharmacotherapy and a stepped approach to interdisciplinarity of chronic pain management.1 The pillars of intervention are medical-technical management, psychosocial interventions and exercise.2
Focusing on medical chronic pain management, Prof Morlion emphasized that pharmacotherapy should target the basic nociceptive process using a combination of different drugs and/or route of administration.4-8 (See Fig. 1)
Figure 1. Different analgesic drug classes and the steps in the pain process they act on.3-8
He reiterated that an ideal analgesic would act rapidly and over a long period of time, minimize interruptions by pain, be effective for a range of pain and patient types and should be tolerable and safe. However realistically, a range of analgesics is required due to the strengths and shortcomings of each.9
Chronic pain usually requires the use of atypical analgesics, still, only 40-50% of patients will achieve at least 30% pain relief.10 Opioids are not to be prescribed for chronic primary pain syndromes (nociplastic) and are not first-line of choice for the neuropathic and nociceptive nature of secondary pain syndromes, as stressed by Prof Morlion.11
Psychosocial management involves training the brain by motivational interviewing, pain neuroscience education, and interventions like cognitive behavioral therapy or acceptance and commitment therapy.12-14
Exercise – another approach to chronic pain management – can also help in pain management. A Cochrane review indicates exercise is best for musculoskeletal and diffuse pain and should be tailored for individual needs.15
Neuropathic and Mixed Pain: A pragmatic best practice approach
Professor Freynhagen presented an approach to mixed pain: any combination of different pain types (nociceptive, neuropathic or nociplastic) simultaneously affecting a certain area.16
Recognizing the difficulty in diagnosing mixed pain, Professor Freynhagen presented painDETECT, a 9-question pain questionnaire to assist clinicians in identifying mixed pain. He also highlighted the potential of painDETECT as a potential pain assessment tool in the Philippines, as it has already been translated into Tagalog and Cebuano.17-18
Professor Freynhagen stressed that the gold standard of mixed pain management continues to be an interdisciplinary and multimodal approach. In pharmacologic management, early treatment targeting both nociceptive and neuropathic pain mechanisms in mixed pain is needed, as addressing either of the mechanisms alone would result in decreased responsiveness.16
With no existing nociceptive and mixed pain pharmacotherapy guidelines, Professor Freynhagen referred to the International Association for the Study of Pain’s recommendations for analgesia in neuropathic pain.19 (See Table 1) Aside from the analgesics, B-vitamins have been studied for their role in nerve repair, but evidence shows their role in pain management is limited.20
Table 1. Recommended analgesics for neuropathic pain by the International Association for the Study of Pain19
Table 1. Recommended analgesics for neuropathic pain by the International Association for the Study of Pain19
In addition to its well-established activity against neuropathic pain, the potential for use of pregabalin against inflammation and inflammatory pain makes it a very promising prospect for mixed pain analgesia.21 Professor Freynhagen also presented some key recommendations for pregabalin use, for pregabalin use in neuropathic pain and in patients with anxiety, impaired sleep, or polypharmacy.22
Common adverse events related to pregabalin use include somnolence and dizziness, but these are usually minor or moderate and resolve in 1 – 2 weeks.23 However, the recreational use or abuse of pregabalin is becoming an increasing concern and so caution should be taken then prescribing pregabalin for patients with a history of substance misuse.22
Prof Freynhagen emphasized to “start low, go slow” with pregabalin dosing. The dose range is 150 to 600 mg per day given in either two or three divided doses. An asymmetrical dosing scheme is also recommended, with a higher evening dose to aid sleep.22
Pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.22
Discontinuation of pregabalin should be considered if no analgesic effect is achieved after 2 weeks of maximum tolerated dose. Onset of angioedema and hypersensitivity however are grounds for immediate discontinuation of pregabalin use and should switch to another first-line drug. The success of pregabalin therapy is affected significantly by patient involvement in treatment planning including pharmacoeducation.22
Combination therapy with other first-line drugs or second line treatment options can be considered in cases with partial response to pregabalin.22,23 Studies have shown that pregabalin combination with duloxetine (COMBO-DN, OPTION-DM) and amitryptilline (OPTION-DM) are promising in peripheral diabetic neuropathic pain.24,25 But while combination therapy is widely practiced, more studies on these regimens are recommended.
Conclusion
Chronic pain management is continuously evolving as the medical community gets closer to deciphering its complexities. While a multimodal and interdisciplinary approach is the recommended standard of care, pharmacotherapy is the anchor from which all other interventions gain traction. Promising evidence has shown pregabalin, by itself or in combination with other first-line analgesics, may be beneficial in addressing the nociceptive and neuropathic mechanisms of mixed pain.
Expert Panel Discussion and Q&A Forum
Local pain experts including Dr Maria Dolma G. Santos, President of the Pain Society of the Philippines, Dr. Emmanuel Perez, President of the Philippine Rheumatology Association, Dr Jose Antonio San Juan, President of the Philippine Orthopedic Society for Sports Medicine and Dr Michael Magabo, Immediate Past President of the Philippine Academy of Rehabilitation Medicine joined the speakers for a panel discussion.
The discussion covered issues commonly seen in the local setting like abrupt self-withdrawal by patients from pregabalin treatment, chronic pain management with pregabalin during the immediate post-operative period, and the incongruence of pain assessment with pain scores.
The speakers were unequivocal in highlighting the risk of self-withdrawal from pregabalin even with reported uneventful abrupt treatment discontinuation. The continuation of pregabalin treatment and close monitoring of pain control in immediate post-operative period were emphasized especially in the context of hyperexcitability in chronic pain sufferers. The speakers together with the panel of experts, strongly recommended the use of specialized pain questionnaires for a more thorough pain assessment.
Ms Audrey Castro, product manager of Viatris’ Philippines concluded the event by reiterating Viatris’ commitment to forge stronger partnerships with healthcare providers and optimism for more quality medical education events.
References: 1. Morlion B, et al. Curr Med Res Opin 2018;34:1169–1178. 2. Morlion B. Nat Rev Neurol 2013;9:462–473. 3. Gilron I, et al. Lancet Neurol 2013;12:1084–1095. 4. Arendt-Nielsen L, et al. Eur J Pain 2018;22:216–241. 5. Kumar s, et al. OA Anaesthetics 2014;2:2. 6. Julius D, et al. Nature 2001;413:203-210. 7. LeeB, et al. Best Pract Res Clin Anaesthesiol 2018;32:101–111. 8. Dunkman WJ, Manning M. Surg Clin North Am 2018;98:1171–1184. 9. Moore N. Acute Pain 2009;11:129–137. 10. Dworkin R, et al. Pain 2007;132:237–251. 11. Hauser W, et al. Eur J Pain 2021;25:949 – 968. 12. Ehde D, et al. Am Psychol 2014;69:153–66. 13. Creswell, J. Annu Rev Psychol 2017;68:491–516. 14. Hughes LS, et al. Clin J Pain 2017;33:552–568. 15. Geneen L, et al. Cochrane Database Syst Rev 2017;4;CD011279 16. Freynhagen R, et al. Curr Med Res Opin 2019;35:1011–1018. 17. Freynhagen, R, et al. Curr Med Res Opin 2020;36:2037–2046. 18. Gomez FC, et al. Neurology Asia 2019;24:21–30. 19. Finnerup N, et al. Lancet Neurol 2015:14:162–173. 20. Paez-Hurtado AM, et al. Nutr Neurosci 2022;14:1–19. 21. Sekiguchi F, et al. Biol Pharm Bull 2018;41:1127–1134. 22. Freynhagen R, et al. Postgraduate Medicine 2021;133:1–9. 23. Freynhagen R, et al. Pain Pract 2015;15:47–57. 24.Tesfaye S, et al. Pain 2013;154:2616–2625. 25. Tesfaye S, et al. Lancet 2022 Aug;400:680–690.
The company’s medical manager, Dr Christian Yap II, introduced the distinguished speakers: Professor Dr Bart Morlion, PhD, DEAA, EDPM of Katholieke Universiteit Leuven in Belgium and Professor Dr Rainer Freynhagen, DEAA, EDPM of Technische Universität München in Germany, who shared their expertise on some novel clinical concepts in chronic pain.
From Acute to Chronic: Chronification and optimizing chronic pain treatment
“Chronification” refers to the progression of transient pain into persistent pain, due to an imbalance between the amplification and inhibition of pain. Neurobiological changes in chronification include peripheral and central sensitization, which can result in reduced threshold for nociceptor activation, leading to greater pain sensations, or hyperalgesia.1
Professor Morlion stressed that chronic pain is more about sensitivity than injury. He also pointed out that genetic, environmental, and biopsychosocial factors can positively or negatively impact the risk, degree, and time-course of chronification.1
To optimize the treatment of chronic pain, Prof Morlion advocated for the early management of acute pain, multimodal pharmacotherapy and a stepped approach to interdisciplinarity of chronic pain management.1 The pillars of intervention are medical-technical management, psychosocial interventions and exercise.2
Focusing on medical chronic pain management, Prof Morlion emphasized that pharmacotherapy should target the basic nociceptive process using a combination of different drugs and/or route of administration.4-8 (See Fig. 1)
Figure 1. Different analgesic drug classes and the steps in the pain process they act on.3-8
He reiterated that an ideal analgesic would act rapidly and over a long period of time, minimize interruptions by pain, be effective for a range of pain and patient types and should be tolerable and safe. However realistically, a range of analgesics is required due to the strengths and shortcomings of each.9
Chronic pain usually requires the use of atypical analgesics, still, only 40-50% of patients will achieve at least 30% pain relief.10 Opioids are not to be prescribed for chronic primary pain syndromes (nociplastic) and are not first-line of choice for the neuropathic and nociceptive nature of secondary pain syndromes, as stressed by Prof Morlion.11
Psychosocial management involves training the brain by motivational interviewing, pain neuroscience education, and interventions like cognitive behavioral therapy or acceptance and commitment therapy.12-14
Exercise – another approach to chronic pain management – can also help in pain management. A Cochrane review indicates exercise is best for musculoskeletal and diffuse pain and should be tailored for individual needs.15
Neuropathic and Mixed Pain: A pragmatic best practice approach
Professor Freynhagen presented an approach to mixed pain: any combination of different pain types (nociceptive, neuropathic or nociplastic) simultaneously affecting a certain area.16
Recognizing the difficulty in diagnosing mixed pain, Professor Freynhagen presented painDETECT, a 9-question pain questionnaire to assist clinicians in identifying mixed pain. He also highlighted the potential of painDETECT as a potential pain assessment tool in the Philippines, as it has already been translated into Tagalog and Cebuano.17-18
Professor Freynhagen stressed that the gold standard of mixed pain management continues to be an interdisciplinary and multimodal approach. In pharmacologic management, early treatment targeting both nociceptive and neuropathic pain mechanisms in mixed pain is needed, as addressing either of the mechanisms alone would result in decreased responsiveness.16
With no existing nociceptive and mixed pain pharmacotherapy guidelines, Professor Freynhagen referred to the International Association for the Study of Pain’s recommendations for analgesia in neuropathic pain.19 (See Table 1) Aside from the analgesics, B-vitamins have been studied for their role in nerve repair, but evidence shows their role in pain management is limited.20
Table 1. Recommended analgesics for neuropathic pain by the International Association for the Study of Pain19
Table 1. Recommended analgesics for neuropathic pain by the International Association for the Study of Pain19In addition to its well-established activity against neuropathic pain, the potential for use of pregabalin against inflammation and inflammatory pain makes it a very promising prospect for mixed pain analgesia.21 Professor Freynhagen also presented some key recommendations for pregabalin use, for pregabalin use in neuropathic pain and in patients with anxiety, impaired sleep, or polypharmacy.22
Common adverse events related to pregabalin use include somnolence and dizziness, but these are usually minor or moderate and resolve in 1 – 2 weeks.23 However, the recreational use or abuse of pregabalin is becoming an increasing concern and so caution should be taken then prescribing pregabalin for patients with a history of substance misuse.22
Prof Freynhagen emphasized to “start low, go slow” with pregabalin dosing. The dose range is 150 to 600 mg per day given in either two or three divided doses. An asymmetrical dosing scheme is also recommended, with a higher evening dose to aid sleep.22
Pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.22
Discontinuation of pregabalin should be considered if no analgesic effect is achieved after 2 weeks of maximum tolerated dose. Onset of angioedema and hypersensitivity however are grounds for immediate discontinuation of pregabalin use and should switch to another first-line drug. The success of pregabalin therapy is affected significantly by patient involvement in treatment planning including pharmacoeducation.22
Combination therapy with other first-line drugs or second line treatment options can be considered in cases with partial response to pregabalin.22,23 Studies have shown that pregabalin combination with duloxetine (COMBO-DN, OPTION-DM) and amitryptilline (OPTION-DM) are promising in peripheral diabetic neuropathic pain.24,25 But while combination therapy is widely practiced, more studies on these regimens are recommended.
Conclusion
Chronic pain management is continuously evolving as the medical community gets closer to deciphering its complexities. While a multimodal and interdisciplinary approach is the recommended standard of care, pharmacotherapy is the anchor from which all other interventions gain traction. Promising evidence has shown pregabalin, by itself or in combination with other first-line analgesics, may be beneficial in addressing the nociceptive and neuropathic mechanisms of mixed pain.
Expert Panel Discussion and Q&A Forum
Local pain experts including Dr Maria Dolma G. Santos, President of the Pain Society of the Philippines, Dr. Emmanuel Perez, President of the Philippine Rheumatology Association, Dr Jose Antonio San Juan, President of the Philippine Orthopedic Society for Sports Medicine and Dr Michael Magabo, Immediate Past President of the Philippine Academy of Rehabilitation Medicine joined the speakers for a panel discussion.
The discussion covered issues commonly seen in the local setting like abrupt self-withdrawal by patients from pregabalin treatment, chronic pain management with pregabalin during the immediate post-operative period, and the incongruence of pain assessment with pain scores.
The speakers were unequivocal in highlighting the risk of self-withdrawal from pregabalin even with reported uneventful abrupt treatment discontinuation. The continuation of pregabalin treatment and close monitoring of pain control in immediate post-operative period were emphasized especially in the context of hyperexcitability in chronic pain sufferers. The speakers together with the panel of experts, strongly recommended the use of specialized pain questionnaires for a more thorough pain assessment.
Ms Audrey Castro, product manager of Viatris’ Philippines concluded the event by reiterating Viatris’ commitment to forge stronger partnerships with healthcare providers and optimism for more quality medical education events.
References: 1. Morlion B, et al. Curr Med Res Opin 2018;34:1169–1178. 2. Morlion B. Nat Rev Neurol 2013;9:462–473. 3. Gilron I, et al. Lancet Neurol 2013;12:1084–1095. 4. Arendt-Nielsen L, et al. Eur J Pain 2018;22:216–241. 5. Kumar s, et al. OA Anaesthetics 2014;2:2. 6. Julius D, et al. Nature 2001;413:203-210. 7. LeeB, et al. Best Pract Res Clin Anaesthesiol 2018;32:101–111. 8. Dunkman WJ, Manning M. Surg Clin North Am 2018;98:1171–1184. 9. Moore N. Acute Pain 2009;11:129–137. 10. Dworkin R, et al. Pain 2007;132:237–251. 11. Hauser W, et al. Eur J Pain 2021;25:949 – 968. 12. Ehde D, et al. Am Psychol 2014;69:153–66. 13. Creswell, J. Annu Rev Psychol 2017;68:491–516. 14. Hughes LS, et al. Clin J Pain 2017;33:552–568. 15. Geneen L, et al. Cochrane Database Syst Rev 2017;4;CD011279 16. Freynhagen R, et al. Curr Med Res Opin 2019;35:1011–1018. 17. Freynhagen, R, et al. Curr Med Res Opin 2020;36:2037–2046. 18. Gomez FC, et al. Neurology Asia 2019;24:21–30. 19. Finnerup N, et al. Lancet Neurol 2015:14:162–173. 20. Paez-Hurtado AM, et al. Nutr Neurosci 2022;14:1–19. 21. Sekiguchi F, et al. Biol Pharm Bull 2018;41:1127–1134. 22. Freynhagen R, et al. Postgraduate Medicine 2021;133:1–9. 23. Freynhagen R, et al. Pain Pract 2015;15:47–57. 24.Tesfaye S, et al. Pain 2013;154:2616–2625. 25. Tesfaye S, et al. Lancet 2022 Aug;400:680–690.