Pharmacogenetic Morphine Spine Study
Condition: Pain
Study type: Observational

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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Children ages 10 to 18, inclusive, years scheduled for spinal surgical procedures.
      
Biospecimen description: 
      De-identified study subjects' genetic information and their responses to pain and pain
      medications, side-effects will be included in a study database. No patient identifiers will
      be included in the database and there will be a confidential (access limited to investigators
      only) code or link between the database and other information about the participant. Repeat
      timed blood samples will be collected using a sparse sampling strategy to evaluate morphine
      and metabolite concentrations. DNA from preoperative blood samples will be analyzed using
      genetic and epigenetic arrays, as well plasma for inflammatory markers.
    
Keywords: Pharmacogenetics; postoperative; pediatric; opioid; perioperative; respiratory depression; chronic pain