449intervals in clinical trials can convey clinically meaningful information regarding
the impact of a pain treatment on health-related quality of life. Individual responder
analyses in clinical trials can improve detection of analgesic activity across patient
groups and within sub-groups, and identify molecular-genetic mechanisms that
contribute to individual variation.
Millennium Laboratories’ Pharmacogenetic Testing is saliva-based testing to
detect genetic variations in enzymes associated with the metabolism of medications
commonly prescribed to patients suffering from debilitating chronic pain and pain-
related effects. This testing will help clinicians identify patients who may benefi t
from modifying the drug selection or dosing of certain prescribed analgesics.
Proove Biosciences’ Drug Metabolism test offers a proprietary Medication
Metabolism Metric to evaluate patients who are slow or fast metabolizers of a drug.
Proove Narcotic Risk is a genetic test to identify patients at increased risk for chem-
ical imbalances in the brain that lead to tolerance, dependence, or abuse of prescrip-
tion pain medications. These tests help select the appropriate analgesic for a patient
and reduce the risk of adverse effects and addiction thus facilitating personalized
management of pain.
Pharmacogenetics of Opioids
Although morphine is the analgesic of choice for moderate to severe cancer pain,
10–30 % of patients do not tolerate morphine. Variations in genes involved in mu-
opioid receptor signaling infl uence clinical response to morphine. Codeine analge-
sia is wholly or mostly due to its metabolism to morphine by the cytochrome P450
enzyme CYP2D6, which shows signifi cant genetic variation in activity. Patients
with a mutation in the gene coding for CYP2D6 will show little or no analgesic
effect from codeine as it requires a properly functioning CYP2D6 to metabolize it
to the active metabolite morphine. Codeine analgesia is less reliable than morphine.
Clinically relevant genetic as well as nongenetic factors infl uencing analgesic
responses and side effects of opioids. These are shown schematically in Fig. 12.6.
Catecholamines are involved in the modulation of pain and are partly metabolized
by the catechol-O-methyltransferase (COMT) enzyme that degrades catecholamines.
Genetic variability in the COMT gene may therefore contribute to differences in pain
sensitivity and response to analgesics. It is shown that a polymorphism in the COMT
gene, Rs4680 (Val158Met), infl uences pain sensitivity in human experimental pain
Table 12.8 P450 isoforms in the metabolism of drugs used in the management of painP450 isoforms Drug category Examples
CYP2D6 Tricyclic antidepressants Amitriptyline, clomipramine, desipramine
Opioid analgesics Codeine, tramadol, oxycodone
CYP2C9 NSAIDs Ibuprofen, diclofenac, naproxen, celecoxib
Antiepileptic drugs Phenytoin
CYP2C19 Antiepileptic drugs Phenytoin
© Jain PharmaBiotech
Personalized Management of Pain