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2007; Anderson & Palmer, 2006), some preliminary estimates for dose adaptations are possible
(Lotsch & Geisslinger, 2006). However, genetic factors must be considered within the context of
the multiple interacting physiological, psychological and environmental factors that influence
responses to pain and analgesia (Kim et al, 2009; Searle & Hopkins, 2009).

1.6.1 Loss of pain sensation
Recognised hereditary syndromes associated with loss of pain sensation include the
'channelopathy‐associated insensitivity to pain' caused by variants in the SCN9A gene, which
codes for the alpha‐subunit of the voltage‐gated sodium channel Na(v)1.7. Na(v)1.7 is located
in peripheral neurons and plays an important role in action potential production in these cells.
Mutations result in loss of Na(v)1.7 function and affected individuals are unable to feel
physical pain (Drenth & Waxman, 2007).
CHAPTER 1 Hereditary sensory and autonomic neuropathy (HSAN) I‐V syndromes are associated with a
range of genetic abnormalities and produce varying patterns of sensory and autonomic
dysfunction and peripheral neuropathy (Oertel & Lotsch, 2008). Hereditary sensory neuropathy
type I (HSN‐I) is a dominantly transmitted sensorimotor axonal neuropathy accompanied by
painless injuries. Hereditary sensory neuropathy type II (HSN‐2) variants result in loss of
sensitivity to touch, pain and temperature (Drenth & Waxman, 2007). Familial dysautonomia is a
congenital sensory and autonomic neuropathy (HSN‐3) that affects the development and
survival of sensory, sympathetic, and some parasympathetic neurons and results in an
indifference to pain and temperature. Hereditary sensory and autonomic neuropathy type IV
(HSAN‐4) is a severe autosomal recessive disorder characterised by childhood onset of
insensitivity to pain and anhidrosis. HSAN‐4 is caused by mutations in the NTRK1 gene coding
for the tyrosine kinase receptor A (Wieczorek et al, 2008). HSAN type V is a very rare disorder. It
is characterised by the absence of thermal and mechanical pain perception caused by a
decreased number of small diameter neurons in peripheral nerves (de Andrade et al, 2008).

1.6.2 Reduced sensitivity to pain
Reduced pain sensitivity has been associated with variants in genes encoding the mu‐opioid
receptor (OPRM1), catechol‐O‐methyltransferase (COMT), guanosine triphosphate
cyclohydrolase 1/dopa‐responsive dystonia (GCH1), transient receptor potential (TRPV 1), and
the melanocortin‐1 receptor (MC1R) (Lotsch et al, 2006).
The mu‐opioid receptor variant N40D which is coded by the single nucleotide polymorphism
(SNP) 118A > G of the OPRM1 gene has been associated with reduced acute pain
responsiveness (Fillingim et al, 2005 Level III‐3; Lotsch et al, 2006 Level IV) but increased exogenous
opioid analgesic requirements (Klepstad et al, 2004 Level III‐3). Intrathecal fentanyl requirements
in labour were reduced in women with the 304G allele but increased in those with the 304A
allele of OPRM1 (Landau et al, 2008 Level III‐3). For additional detail related to individual opioids
see Section 4.1.2.
COMT metabolises noradrenaline, adrenaline, and dopamine, and has recently been
implicated in the modulation of pain. COMT inhibition may lead to increased pain sensitivity
via beta‐adrenergic receptor dependent mechanisms (Nackley et al, 2007). Haplotypes with high
COMT activity are associated with low pain sensitivity to mechanical and thermal stimuli
(Diatchenko et al, 2005). The Val158Met polymorphism influences the activity of the COMT
enzyme. In cancer pain, carriers of COMT Val/Val and Val/Met genotypes had higher morphine
requirements than carriers of the Met/Met genotype (Reyes‐Gibby et al, 2007 Level III‐3).
GCH1 is the rate‐limiting enzyme for tetrahydrobiopterin (BH4) synthesis, an essential cofactor
in the biosynthesis of biogenic amines and nitric oxide. It is a key modulator of peripheral

22 Acute Pain Management: Scientific Evidence