448
Genetic Mutations with Loss of Pain
Complete prevention of pain has so far been seen in 6 distinct rare hereditary syn-
dromes: the ‘channelopathy-associated insensitivity to pain’, caused by 13 currently
identifi ed variants in the SCN9A gene coding for the alpha-subunit of the voltage-
gated sodium channel, and 5 of the hereditary sensory and autonomic neuropathy
(HSAN) I-V syndromes, caused by various mutations in several genes (Oertel and
Lötsch 2008 ). Reduced pain in the average population has been associated with
frequent variants in the micro-opioid receptor gene (OPRM1), catechol-O-
methyltransferase gene (COMT), guanosine triphosphate cyclohydrolase 1/dopa-
responsive dystonia gene (GCH1), transient receptor potential cation channel,
subfamily V, member 1 gene (TRPV1) or the melanocortin-1 receptor gene (MC1R).
Duplications/amplifi cations of the cytochrome P450 2D6 (CYP2D6) gene leading
to increased enzyme function may cause intense opioid effects of codeine up to
toxicity. The COMT V158M variant has been associated with decreased morphine
requirements for analgesia. Inactivating MC1R variants have been associated with
increased opioid analgesia of the micro-opioid receptor agonist morphine-6-
glucuronide and, in women only, of kappa-opioid agonists. Finally, variants in the
P-glycoprotein gene (ABCB1) conferring decreased transporter function have been
associated with increased respiratory depressive effects of fentanyl. In conclusion,
a number of genetic variants that prevent pain by decreasing nociception or increas-
ing analgesia have been identifi ed. Given the complex biological and psychological
nature of pain, the interindividual variance in pain and analgesia due to identifi able
genetic causes, should be taken into consideration in personalizing pain therapy.
Pharmacogenetics/Pharmacogenomics of Pain
More recently, there has been a growing body of evidence demonstrating differ-
ences in analgesic response to various pharmacotherapies, although the source of
this variability largely remains to be explained. To this end, basic science research
is beginning to identify the allelic variants that underlie such antinociceptive vari-
ability using a multiplicity of animal models, and powerful genetic approaches are
being exploited to accelerate this process. There is already a growing body of evi-
dence demonstrating differences in analgesic response to various pharmacothera-
pies, although the source of this variability largely remains to be explained. P450
isoforms involved in the metabolism of some drugs used in the management of pain
are shown in Table 12.8.
Although the vast majority of these studies have focused on the pharmacogenet-
ics of opioids, owing to their prominent status as analgesics, the number of
pharmacotherapies evincing genetically-based variability is rapidly expanding. In
addition, analogous studies have been undertaken in humans, as a small but grow-
ing number of clinical trials have begun to evaluate prospectively the existence, if
often not the origin, of interindividual differences in analgesic drug response.
Presentation of the spectrum of individual responses and associated prediction
12 Personalized Management of Neurological Disorders