The descending pain modulation system predicts short term efficacy of multimodal pain therapy: an observational prospective cohort study

ABSTRACT

Objectives

Treating chronic pain patients with multimodal pain therapy (MMPT) alters perception, awareness, and processing of pain at multiple therapeutic levels. Several clinical observations suggest that the effects of therapy may go beyond the possible sum of each level of therapy and may be due to a central descending inhibitory effect measurable by conditioned pain modulation (CPM). Thus, we investigated whether CPM is able to identify a group of patients that benefit particularly from MMPT.

Methods

This was an observational prospective cohort study. Patients were hospitalized on a special pain medicine ward with specially trained staff for 10 days. The patients were questioned and had investigations before and shortly after MMPT and were followed-up on 3 months post discharge. Before and after treatment, subjects were investigated via CPM and quantitative sensory testing (QST) as well as completing questionnaires. The study was registered in the German Clinical Trials Register (DRKS00006850).

Results

During the study period of 24 months, 224 chronic pain patients were recruited. 51 percent of patients completed the study period. There was an improvement in overall groups regarding all domains assessed, lasting beyond the end of the intervention. Patients with a sufficient CPM effect, defined as a reduction in pain during the conditioning stimulus, at baseline did show a more pronounced reduction in mean pain ratings than those without. This was not the case 3 months after therapy. Furthermore, sufficient CPM was identified as a predictor for pain reduction using a linear regression model.

Conclusion

In conclusion, this study shows that while a heterogeneous group of patients with chronic pain disorders does sustainably benefit from MMPT in general, patients with a sufficient CPM effect do show a more pronounced decrease in pain ratings directly after therapy in comparison to those without.

PLAIN LANGUAGE SUMMARY

Pain at one body site can be reduced, when another painful stimulus occurs at the same time. This mechanism is referred to as conditioned pain modulation (CPM).

Some patients with chronic pain are treated using different methods such as medication, physiotherapy, and patient education in an in-patient setting, referred to as multimodal pain therapy (MMST). To improve pain therapy, it is vital to identify whether patients who respond especially well to a certain treatment show specific characteristics (i.e. mechanism-based therapy). We investigated whether the prospect of success of MMST is related to how well CPM works in patients. We assessed the CPM effect and sensory function of 224 patients with chronic pain before and after therapy to answer this question. Additionally, patients completed questionnaires about their pain, mood, quality of life, and sleep directly after therapy and three months later. All patients showed improvement after therapy, but in those in which CPM worked well, pain was reduced stronger than in those in which CPM did not. Three months after treatment, the difference disappeared.

KEYWORDS:

• Conditioned pain modulation
• multimodal pain therap
• chronic pain
• predictors
• quantitative sensory testing
• questionnaires
• diffuse noxious inhibitory control
• mechanism-based pain therapy
• responders

Acknowledgments

We would like to thank our student assistants Swantje Jendral and Lena Rhode for their help in data processing and Dilâra Kersebaum for language editing.

Declaration of funding

The study was granted by Asklepios Forschungsförderung (Asklepios research foundation).

Disclosure of financial/other conflicts of interest

MS has received personal fees from Sanofi Genzyme, Grünenthal GmbH, Amicus and Takeda, outside the submitted work.

FL has received personal fees from Berlin-Chemie and Roche, outside the submitted work.

DF, JM and SK report no conflicts of interest.

JF reports a grant (FO1311/1-1) from the German Research Foundation (DFG), personal fees and non-financial support from Grünenthal GmbH, personal fees from Bayer and non-financial support from Novartis, outside the submitted work.

AB has received consultant fees from Bayer as well as personal fees from Bristol-Meyer-Squibb and Pfizer, outside the submitted work.

RB has received grants from EU Projects: „”European“ (115,007). DOLORisk (633,491). IMI Paincare (777,500).

German Federal Ministry of Education and Research (BMBF): Verbundprojekt: Frühdetektion von Schmerzchronifizierung (NoChro) (13GW0338C).

German Research Network on Neuropathic Pain (01EM0903).

Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG., Novartis Pharma GmbH, Alnylam Pharmaceuticals Inc., Zambon GmbH, Sanofi-Aventis Deutschland GmbH. He received speaker fees from Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co.Ltd., Lilly GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Astellas Pharma GmbH, Desitin Arzneimittel GmbH, Teva GmbH, Bayer-Schering, MSD GmbH, Seqirus Australia Pty. Ltd, Novartis Pharma GmbH, TAD Pharma GmbH, Grünenthal SA Portugal, Sanofi-Aventis Deutschland GmbH, Agentur Brigitte Süss, Grünenthal Pharma AG Schweiz, Grünenthal B.V. Niederlande, Evapharma, Takeda Pharmaceuticals International AG Schweiz, Ology Medical Education Netherlands. He received consultant fees from Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co. KG, Astellas Pharma GmbH, Novartis Pharma GmbH, Bristol-Myers Squibb, Biogenidec, AstraZeneca GmbH, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals S.A., Seqirus Australia Pty. Ltd, Teva Pharmaceuticals Europe Niederlande, Teva GmbH, Genentech, Mundipharma International Ltd. UK, Astellas Pharma Ltd. UK, Galapagos NV, Kyowa Kirin GmbH, Vertex Pharmaceuticals Inc., Biotest AG, Celgene GmbH, Desitin Arzneimittel GmbH, Regeneron Pharmaceuticals Inc. USA, Theranexus DSV CEA Frankreich, Abbott Products Operations AG Schweiz, Bayer AG, Grünenthal Pharma AG Schweiz, Mundipharma Research Ltd. UK, Akcea Therapeutics Germany GmbH, Asahi Kasei Pharma Corporation, AbbVie Deutschland GmbH & Co. KG, Air Liquide Sante International Frankreich, Alnylam Germany GmbH, Lateral Pharma Pty Ltd, Hexal AG, Angelini, Janssen, SIMR Biotech Pty Ltd Australien.

The authors have no other relevant conflicts of interest to disclose.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.