Pharmacogenetic Morphine Spine Study
Pharmacogenetic Morphine Spine Study
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.
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.
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.