Effects and adverse events of opioids: a study on the role of pharmacokinetic and pharmacogenetic heterogeneity.

Pain is one of the most frequent symptoms in cancer patients. A majority of
these patients need treatment with opioids. In case of moderate-severe pain,
strong opioids, step 3 medication from the WHO ladder, are indicated. However,
in some patients treated with an opioid of first choice, adequate pain relief
without dose-limiting side effects will not be reached. Delirium is one of the
most serious side effects. In case of dose-limiting side effects and/or
inadequate pain relief, opioid rotation is advised in the Dutch CBO guideline.
In case of opioid rotation, the opioid of first choice is changed into another
opioid. However, for an individual patient it is not possible to determine
which opioid is best for him/her, because the mechanisms underlying the failure
of achieving pain relief or the induction of side effects are not known.
Treatment, therefore, is based on trial and error. Genetic polymorphism has
been suggested to be responsible for the various responses on opioids in
individual patients, either on the level of the metabolism (absorption,
distribution, metabolism and axcretion), or on the level of the central nervous
system. Scientific reports, however, are scarce and only limited to morphine.

To study the underlying demographic, clinical and pharmacogenetic factors
contributing to the failure of achieving analgesia and/or the occurrence of
dose-limiting side effects in individual cancer patients for seperate opioids;
- To study if the demographic, clinical and pharmacogetic factors contributing
to the failure of specific opioids with respect to the achievement of analgesia
and/ the occurrence of side effects determine the effect of rotation to another
opioid in individual patients;
- To delelop a strategy for opioid rotation with respect to the type of the
opioid rotated to and its dose in case of failure on primary treatment with a
specific opioid in an individual patient.

This is a two-year prospective cohort study in which about 1000 cancer
patients regularly treated with strong opioids for moderate-severe nociceptive
pain will be monitored daily for pain intensity and the occurrence of side
effects. In case of dose-limiting side effects and/or inadequate pain relief,
opioid rotation will be used; the type of opioid and the route of
administration will be choosen according to the clinical situation and the
opinion of the responsible caregiver. After infomed consent is given blood will
be taken for pharmacogenetic analyses measuring *single nucleotide polymorfisms
(SNPs) with possible relevance for the metabolism of opioids and its effects in
the central nervous sytem. Patients admitted to the unit for palliative care
and symptom control in Erasmus MC Daniel den Hoed Cancer Center will also be
asked informed consent to take blood samples for pharmacokinetic analyses of
the opioids given. In case of informed consent, blood samples will be taken at
specific times during a period of 72 hours after a change in the opioid
regimen. The opioids used and their metabolites wil be measured. Opioids and
metabolites will also be measured in urine. All clinical and demogaphic data,
measurements of pain and side effects and the measurements of SNIP's and
pharmacikinetic analyses will be coupled in a database for further analysis of
research questions.

Patienst will be treated regurarly with strong opioids. Nurse will monitor the
effect of the opioids by asking the patients the intensity of pain and side
effects. This monitoring also is a standard procedure.
For the study of the pharmacogenetis and pharmacokinetics extra effort is
asked. Blood for pharmacogenetics is taken by a single venapuncture (15 ml).
However, for the study of the pharmacokinetics more samples are needed. In that
case an intravenous canula will be placed for blood sampling. During 72 hours
after a change in the opioid regimen blood samples will be taken twice a day.
In case of rescue medication use, 5 extra samples will be taken around the
administration of rescue opioid medication. Because the baseline sample then
should be taken before the administration of the rescue medication, the
delivery of rescue medication may be somewhat postponed.