Pharmacogenetic Morphine Spine Study

NCT ID: NCT01839461

Last Updated: 2019-10-07

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 137 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2009-07-31
• Study Completion Date: 2019-04-02

Brief Summary

The purpose of this research study is to identify factors and genes (the DNA material that determines the makeup of the human body) that may be associated with how children cope with pain and respond to pain medication. Morphine is a pain medication commonly prescribed after this surgery during the hospital stay. The investigators want to study factors that may be associated with morphine requirement after surgery and side-effects from morphine. They will use pharmacometric models to identify dosing guidelines and factors associated with individual variability in metabolism and efficacy/safety of morphine. They will also study psychological, genetic and epigenetic factors associated with acute and chronic post-surgical pain after spine surgery. The investigators expect that the information obtained in this research study will help to develop effective, safer, and tailored treatment options in the future.

Detailed Description

Safe and effective analgesia is an important unmet medical need in children. Despite efforts to promote non-pharmacologic interventions, drug treatment remains the standard of care for children experiencing severe pain following surgery. Inadequate pain relief after invasive surgery, and side effects from analgesics such as morphine occur frequently in up to 50% of children. A study of patient-controlled analgesia morphine use after spine surgery in adolescents observed a 45% incidence of postoperative nausea and vomiting 15% incidence of pruritis and 7% incidence of respiratory depression. Among the drugs available, the opioids, specifically morphine is the most commonly employed. Morphine has a narrow therapeutic index, with the most fatal toxicity being respiratory depression. For morphine, like most opioids, there is a fine balance in dosing regimen between optimal pain control and safety in terms of decreasing morphine's respiratory depressant/ sedative side effects. Inadequate pain relief and analgesic side effects have major clinical, behavioral and economic consequences. Neither evidence-based dosing guidelines nor rigorous documentation of therapeutic benefit for morphine has been ascertained in the pediatric patient population. Despite aggressive pain management after spine surgery, findings showed that neither children's pain nor their analgesic use diminished significantly over time. As such, there is a critical knowledge gap in the medical literature that significantly impacts the pediatric pain management. In recognition of this therapeutic challenge the investigators plan to evaluate the determinants of inter-individual differences in opioid analgesic responsiveness and adverse effects in children. Adolescents following spine surgery have a great variability in morphine requirements with greater use as they became older. Analgesic dosing is dependent on appreciation of the interplay between pharmacokinetics, pharmacodynamics and therapeutics. These factors are often poorly understood, where the effective control of procedural pain for example, remains problematic. Suitable pharmacological alternatives to opioid treatment for moderate to severe pain in children after surgery are limited and consequently there is a need for a critical evaluation of the existing opioids and research reports.

Recently a number of small studies have shown the association of single nucleotide polymorphism in genes in the pain pathway, with altered pain response to a stimulus or altered response to opioids following a painful procedure. Age, gender, cultural influences, anxiety, type of surgical procedure and genetic factors can all influence the response. By extending follow up of patients to years after surgery, the aims were amended to include evaluation of chronic post-surgical outcomes.

We will be collecting data on pain scores, opioid effects, psychological questionnaires, blood samples and pupillometry data.

Conditions

Pain

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Eligibility Criteria

Inclusion Criteria

• Children aged 10 to 18, inclusive, years of age
• Diagnosis of Idiopathic scoliosis, kyphosis and/or kyphoscoliosis
• Scheduled for spine fusion

Exclusion Criteria

• Known hypersensitivity to morphine
• Patients on chronic pain medication.
• Pregnant or breastfeeding females.
• Children with a history of or active renal or liver disease.
• Concomitant use of medication known to induce or inhibit CYP2D6 activity including paroxetine, fluoxetine, cimetidine, duloxetine or methadone.
• Non-English speaking patients.
• Developmental delay.
• Children who have problems with pupil or pupillary reaction due to disease (such as amyloidosis, bilateral Horner's syndrome, familial dysautonomia, other major neurological disorders) or preoperative medications influencing pupillary size (anti-cholinergic, narcotic medications such as codeine in cough syrup) will be recruited but pupillometry will be deferred.

• Minimum Eligible Age: 10 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Vidya Chidambaran, MD

Role: PRINCIPAL_INVESTIGATOR

Cincinnati Childrens Hospital Medical Center

Locations

Cincinnati Childrens Hospital Medical Center

Cincinnati, Ohio, United States

Countries

United States

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Einhorn LM, Monitto CL, Ganesh A, Duan Q, Lee J, Ramamurthi RJ, Barnett K, Ding L, Chidambaran V. Multi-Institutional Study of Multimodal Analgesia Practice, Pain Trajectories, and Recovery Trends After Spine Fusion for Idiopathic Scoliosis. Anesth Analg. 2025 Nov 1;141(5):1137-1148. doi: 10.1213/ANE.0000000000007351. Epub 2025 Jan 2.

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Chidambaran V, Zhang X, Pilipenko V, Chen X, Wronowski B, Geisler K, Martin LJ, Barski A, Weirauch MT, Ji H. Methylation quantitative trait locus analysis of chronic postsurgical pain uncovers epigenetic mediators of genetic risk. Epigenomics. 2021 Apr;13(8):613-630. doi: 10.2217/epi-2020-0424. Epub 2021 Apr 6.

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Chidambaran V, Ding L, Moore DL, Spruance K, Cudilo EM, Pilipenko V, Hossain M, Sturm P, Kashikar-Zuck S, Martin LJ, Sadhasivam S. Predicting the pain continuum after adolescent idiopathic scoliosis surgery: A prospective cohort study. Eur J Pain. 2017 Aug;21(7):1252-1265. doi: 10.1002/ejp.1025. Epub 2017 Mar 27.

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Chidambaran V, Venkatasubramanian R, Zhang X, Martin LJ, Niu J, Mizuno T, Fukuda T, Meller J, Vinks AA, Sadhasivam S. ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children. Pharmacogenomics J. 2017 Mar;17(2):162-169. doi: 10.1038/tpj.2015.98. Epub 2016 Jan 26.

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Other Identifiers

2009-0973

Identifier Type: -

Identifier Source: org_study_id