Mar 15, 2026
Pharmacogenetic determinants of response to analgesic and co-analgesic treatments in chronic pain: a systematic review.
- Camille Racca1,
- Julia Franken2,
- Ada Du Pasquier1,
- Marion Cahen1,
- Ihssene Djidjeli2
- 1Pitié-Salpêtrière Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France;
- 2Clinical Research Committee, Rare Disease Pain Network (REDOMA), Paris, France.
Protocol Citation: Camille Racca, Julia Franken, Ada Du Pasquier, Marion Cahen, Ihssene Djidjeli 2026. Pharmacogenetic determinants of response to analgesic and co-analgesic treatments in chronic pain: a systematic review.. protocols.io https://dx.doi.org/10.17504/protocols.io.rm7vz4q4xlx1/v1
License: This is an open access protocol distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Protocol status: Working
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Created: March 15, 2026
Last Modified: March 15, 2026
Protocol Integer ID: 313302
Keywords: potential pharmacogenetic predictors of analgesic effectiveness, pharmacogenetic determinants of therapeutic response, potential pharmacogenetic predictor, different chronic pain condition, pharmacogenetic determinants of response, safety across different chronic pain condition, investigating pharmacogenetic determinant, personalized approaches to chronic pain management, analgesic effectiveness, chronic pain management, pharmacogenetic determinant, overview of genetic variant, chronic pain, genetic variant, analgesic, variability in treatment response, pharmacological treatment
Abstract
This protocol describes a systematic review investigating pharmacogenetic determinants of therapeutic response to pharmacological treatments used in chronic pain, including both analgesic and co-analgesic medications. The review will synthesize evidence on the association between germline genetic variants and treatment effectiveness or safety across different chronic pain conditions.
The expected results will provide an overview of genetic variants associated with variability in treatment response and adverse effects, helping to identify potential pharmacogenetic predictors of analgesic effectiveness. These findings may contribute to improving personalized approaches to chronic pain management.
Guidelines
This systematic review will be conducted and reported in accordance with the PRISMA guidelines. As the review will include primarily observational studies, the reporting quality of included studies will also be considered in light of the STROBE recommendations.
Materials
The following materials and resources will be required for the conduct of this systematic review:
- Access to bibliographic databases: PubMed/MEDLINE, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL)
- Reference management software for citation storage and duplicate removal (e.g., Zotero, EndNote, or Mendeley)
- Screening and systematic review management software (e.g., Rayyan, Covidence, or similar tools)
- Data extraction forms developed for the review (spreadsheet or database format)
- Risk of bias assessment tools, including the Joanna Briggs Institute (JBI) critical appraisal checklists
- Access to statistical and data management software if required (e.g., R, Jamovi, or similar software)
Troubleshooting
Safety warnings
Ensure that all team members are familiar with the PRISMA 2020 guidelines and the STROBE recommendations for observational studies.
Secure access to the required bibliographic databases, including PubMed/MEDLINE, Embase, and Scopus.
Define reviewer roles in advance, including dual independent screening and dual independent data extractionprocedures.
At least one reviewer with methodological expertise in systematic reviews should be involved in the study design and methodological oversight.
Ethics statement
No primary data will be collected, and no direct contact with human participants will occur. Therefore, formal ethical approval is not expected to be required. Reviewers will follow predefined eligibility criteria, screening procedures, and data extraction methods to ensure consistency and reproducibility. Any deviations from the protocol will be documented and reported transparently in the final manuscript.
Review question
What is the effect of germline genetic variants on the effectiveness and safety of pharmacological treatments used for chronic pain?
Primary Objective
To evaluate the effect of germline genetic variants on the therapeutic effectiveness of pharmacological treatments used in chronic pain, including both analgesic and co-analgesic medications.
Therapeutic effectiveness will be assessed using outcomes such as:
- reduction in pain intensity
- treatment response according to validated pain scales
- changes in analgesic dose requirements
- need for treatment escalation
Genetic variants may be associated with either increased therapeutic response or reduced treatment effectiveness.
Secondary Objectives
To evaluate the effect of genetic variants on adverse drug reactions associated with analgesic and co-analgesic treatments.
To assess whether pharmacogenetic effects differ according to drug class, including:
- opioids
- antidepressants used as co-analgesics
- antiepileptic drugs used for pain management
- To explore whether pharmacogenetic effects differ according to drug class or type of chronic pain.
- To explore differences in pharmacogenetic associations across pain conditions, such as:
- neuropathic pain
- musculoskeletal pain
- fibromyalgia
- cancer-related chronic pain
Population
This review will include studies involving adults or children experiencing chronic pain, defined as pain persisting or recurring for at least three months in accordance with the definition proposed by the International Association for the Study of Pain.
Eligible pain conditions include, but are not limited to:
- neuropathic pain
- small fiber neuropathy
- erythromelalgia
- chronic musculoskeletal pain
- chronic low back pain
- fibromyalgia
- chronic pelvic pain
- chronic cancer-related pain
Studies including mixed populations will be considered eligible if outcomes for individuals with chronic pain are reported separately or if individuals with chronic pain constitute the majority of the study population.
Types of Interventions
All pharmacological treatments used in the management of chronic pain will be considered eligible.
These include, but are not limited to:
- analgesics, particularly opioids (e.g., morphine, tramadol, oxycodone, codeine)
- antidepressants used as co-analgesics, including tricyclic antidepressants and serotonin–norepinephrine reuptake inhibitors
- antiepileptic drugs used for pain management, such as gabapentin, pregabalin, carbamazepine, or oxcarbazepine
Other pharmacological treatments used for chronic pain may also be included if studies evaluate the association between genetic variants and treatment effectiveness.
Types of studies
Included studies
The review will include the following study designs:
- randomized controlled trials;
- non-randomized interventional studies;
- prospective and retrospective cohort studies;
- case–control studies;
- analytical cross-sectional studies;
- case series including at least five participants.
Excluded studies
The following types of publications will be excluded:
- animal studies;
- in vitro studies;
- expert opinions;
- narrative reviews;
- editorials and commentaries;
- conference abstracts for which sufficient data cannot be extracted.
Studies investigating only genetic susceptibility to pain without evaluating treatment response will be excluded.
Search Strategy
A comprehensive literature search will be conducted in PubMed/MEDLINE, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) using a combination of controlled vocabulary (e.g., MeSH and Emtree terms) and free-text keywords related to chronic pain, pharmacological treatments for pain, and pharmacogenetics.
The search strategy will be adapted for each database.
Reference lists of relevant articles and reviews will also be screened to identify additional eligible studies..
Screening strategy
All retrieved records will be imported into a reference management software and duplicates will be removed.
The study selection process will consist of two stages:
- Title and abstract screening
- Full-text eligibility assessment
Each stage will be performed independently by two reviewers.
Disagreements will be resolved through discussion or consultation with a third reviewer.
The study selection process will be reported using a PRISMA flow diagram.
Data Management
Extracted data will include:
- study characteristics (year, country, design)
- participant characteristics
- type of chronic pain
- pharmacological treatment evaluated
- genetic variants analyzed
- outcome measures
- effect estimates and statistical results
Data extraction will be conducted independently by two reviewers.
Statistical Methods
A narrative synthesis will be conducted to summarize the evidence regarding pharmacogenetic determinants of treatment response to pharmacological treatments used in chronic pain.
Given the expected heterogeneity in genetic variants, pharmacological treatments, pain conditions, and outcome measures, a meta-analysis is not planned.
Findings will therefore be summarized using a structured narrative approach, highlighting associations between specific genetic variants and treatment effectiveness.
Risk of Bias Assessment
Risk of bias will be assessed independently by two reviewers using the Joanna Briggs Institute (JBI) critical appraisal checklists, according to the study design.
The appropriate JBI checklist will be applied for each study type, including:
- randomized controlled trials
- cohort studies
- case–control studies
- cross-sectional studies
- case series
Disagreements between reviewers will be resolved through discussion or consultation with a third reviewer.
The results of the risk of bias assessment will be presented in tabular form.
Support and Funding
This review is supported by DRAW YOUR FIGHT, a nonprofit organization dedicated to raising awareness of invisible disabilities and chronic pain, and to promoting research through collaboration between patients and medical experts.
The review received no specific external funding.
Protocol references
Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or a disease: the IASP classification of chronic pain for the International Classification of Diseases (ICD-11). Pain. 2019;160(1):19–27.
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–1457.
Aromataris E, Munn Z (Editors). JBI Manual for Evidence Synthesis. Joanna Briggs Institute; 2020
Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and opioid therapy. Clinical Pharmacology & Therapeutics. 2021;110(4):888–896.
Stamer UM, Stüber F. The pharmacogenetics of analgesia. Expert Opinion on Pharmacotherapy. 2007;8(14):2235–2245.
Acknowledgements
The authors acknowledge the support of their institutions and colleagues who contributed to methodological discussions during the development of this protocol.