There is significant inter-individual variation in response to morphine in terms of analgesia
and side-effects. In recent years there has been growing interest in the possibility that genetic
factors may play a role in variability in morphine response.
The aims of this thesis were to develop a clinically relevant method of defining response to
morphine, to investigate how multiple clinical and genetic factors may interact together to
influence response to morphine and to explore constipation as a common side-effect of
morphine.
Clinical and biological data were collected as part of two clinical trials: 1) A prospective
observational study which included patients taking oral morphine for cancer pain (N=298)
and 2) A prospective follow-up randomised controlled trial of oral morphine versus oral
oxycodone for cancer pain (recruitment ongoing). Symptom complexes were examined using
Principal Components Analysis. Genetic association testing was carried out using both the
candidate gene approach (sequence-specific primers with polymerase chain reaction) and
genome-wide assays. Multivariate regression analyses were used to explore gene-gene and
gene-environment interactions. Preliminary testing of a constipation assessment tool was
performed.
Analgesic response and central side-effects appear to be distinct components of morphine
response. The genetic and clinical factors associated with these clinical outcomes and with
daily morphine dose requirements are markedly different.
There is inter-individual variation in bowel function in cancer patients on oral morphine.
Constipation is a common symptom and is generally poorly managed.
It is too early to be able to apply the results of genetic association studies of morphine
response in cancer pain to clinical practice. Response to morphine is complex, both in terms
of clinical confounders and pharmacogenetics. Challenges for future research include
carrying out carefully designed studies of adequate power, standardising outcome measures
of response to morphine and expansion of the genetic association testing.