Table 2.

Trials assessing the influence of gene polymorphisms associated with neurotransmission on drug response in humans.

Gene	Refernces	Drugs	Polymorphisms	Populations	Results
	Laugsand et al., 2011 [21]	Opioids (morphine, oxycodone, fentanyl, others)	rs4680, rs4633	n = 1579 cancer patients (European Caucasians) from the cohort of [22]	C allele of rs165722, the T allele of rs4633 and the G allele of rs4680 had less nausea/vomiting
	Reyes-Gibby et al., 2007 [23]	Morphine	rs4680	n = 207 cancer	Carriers of val/val and val/met genotype required 63% and 23%, respectively, higher morphine dose compared to carriers of met/met genotype
	Lötsch et al., 2009 [24]	Various opioids		n = 352 patients with chronic pain of various origin	No association
COMT	Klepstad et al., 2011 [22]	Morphine (n = 830), oxycodone (n = 446), fentanyl (n = 699), or other opioids (n = 234)	112 SNPs in the 25 candidate genes including OPRM1 A118G	n = 2294 cancer patients, European Caucasians	None of SNPs in the candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1,  COMT,  HRH1,  ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose
	Rakvåg et al., 2008 [25]	Morphine	11 SNP and haplotypes, including rs4680, rs4633 not included	n = 197 Caucasian cancer patient cohort receiving oral morphine treatment for cancer pain	The most frequent haplotype (34.5% rs2075507, rs737866, rs7287550R, rs5746849, rs740603, rs6269, rs2239393, rs4818, rs4680 (Val158Met) rs174699, rs165728 GACAAAACATT) associated with lower morphine doses, with a reduction factor of 0.71
	Ross et al., 2008 [26]	Morphine	13 SNPs, rs4818 not included	n = 228 cancer patients on morphine	Haplotype in intron 1 (AATTGAAATAATT) and 4873G genotype (10% is strongly associated with somnolence), hallucinations and confusion after treatment with morphine (protective effect). ABCB1 genotypes and haplotypes investigated in the study as well allele 21/2677G and 12/1236C associated with somnolence, hallucinations, and confusion after treatment with morphine (protective effect)
	Reyes-Gibby et al., 2007 [23]	Morphine	A118G	n = 207 cancer patients, Caucasians	GG genotype required 93% higher morphine dose compared to carriers of AA genotypes (P = 0.012)
	Klepstad et al., 2004 [10]	Morphine	A118G	n = 99 cancer patients, Caucasians	No association with the intensities of symptoms such as fatigue, nausea and vomiting, dyspnea, sleep disturbance, loss of appetite, and constipation were similar between the three cohorts, The serum concentrations of morphine, M6G, and M3G were higher in patients homozygous for the 118G allele
	Campa et al., 2008 [27]	Morphine	A118G	n = 145 Italian Caucasians	Significant association of pain relief after treatment with morphine with the allele. The association improved with the combination of the allele and polymorphism in ABCB1 detection of three groups: strong responders, responders, and nonresponders, sensitivity  →→ 100%, specificity > 70%
	Lötsch et al., 2009 [24]	Various opioids	A118G	n = 352 patients with chronic pain of various origin	Tendency towards increased pain in dose-dependent manner with the μ-opioid receptor variant 118G. Daily opioid doses significantly decreased in a gene dose-dependent manner with the P-glycoprotein variant ABCB1 3435C>T
OPRM1	Liu and Wang 2012 [28]	Acetaminophen/ tramadol	A118G	n = 96 patients with adenocarcinoma of the colon or rectum (n = 84), or stomach (n = 12) who developed oxaliplatin-induced painful neuropathy	The requirement for rescue analgesia higher for patients with G allele, AA genotype-better analgesic effect than G allele variants (AG or GG genotypes). Pretreatment and posttreatment VAS scores for patients with G allele variants were 3.1 and 2.6, respectively; for patients with AA genotype, pretreatment and posttreatment VAS scores were 3.0 and 0.9
	Janicki et al., 2006 [13]	Morphine	A118G	n = 121 chronic, noncancer pain patients, Caucasians	The mean opioid dose is significantly larger in the homozygous carriers of the wild-type 118A allele when compared with the carriers of the variant allele
	Klepstad et al., 2011 [22]	Morphine (n = 830), oxycodone (n = 446), fentanyl (n = 699), or other opioids (n = 234)	112 SNPs in the 25 candidate genes including OPRM1 A118G	n = 2294 cancer patients, European Caucasians	None of SNPs in the candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1,  COMT,  HRH1,  ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose
	Droney et al., 2013 [29]	Morphine	A118G	n = 264 cancer patients taking oral morphine	Genetic factors only accounted for 12% of variability in residual pain on morphine and 3% of variability in central side effects
CREB1	Nishizawa et al., 2012 [30]	Opioids			rs2952768 was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery
HTR3B	Laugsand et al., 2011 [21]	Opioids (morphine, oxycodone, fentanyl, and others)	rs1176744, rs3782025 rs1672717	n = 1579 cancer patients (European Caucasians)	G allele of rs1176744, the T allele of rs3782025, and the T allele of rs1672717 were associated with less nausea/vomiting
CHRM3	Laugsand et al., 2011 [21]	Opioids (morphine, oxycodone, fentanyl, and others)	rs10802789 rs685550	n = 1579 cancer patients (European Caucasians)	T allele of rs10802789 associated with more nausea/vomiting
KCNJ6	Lötsch et al., 2010 [31]	Methadone	rs2070995	n = 352 opioid-treated chronic pain patients	The daily methadone substitution doses during the first therapy year were larger in the rs2070995 AA genotype (n = 4, 119.7 ± 49.6 mg/day) than in other rs2070995 genotypes (77.5 ± 26.2 mg/day, P = 0.003)
DRD4	Ho et al., 2008 [32]	Heroin	−521C/T	n = 43 current heroin uses, 66 controls	TT control subjects had lower pain threshold versus CC/CT controls and versus TT addicts
HTR2C	Brash-Andersen et al., 2011 [33]	Escitalopram	rs6318	n = 34 patients with peripheral neuropathic pain	rs6318 (Cys23Ser) in the HTR2C gene showed significant association with treatment response in men, with 75% carrying the C allele being responders. The same tendency was seen in women

VAS: visual analogue scale. CREB1: cAMP responsive element binding protein 1 encodes a transcription factor, a member of the leucine zipper family of DNA binding proteins. HTR3B: 5-hydroxytryptamine (serotonin) receptor 3B encodes subunit B of the type 3 receptor for serotonin (neurotransmitter, hormone, and mitogen). Activation of the receptor leads to fast depolarizing responses in neurons. Pentaheteromeric complex with subunit A (HTR3A) displays the full functional features of this receptor. HTR2C encodes the 2C subtype of serotonin receptor. CHRM3: the muscarinic cholinergic receptor 3, G-protein-coupled receptor controls smooth muscle contraction, and its stimulation increases secretion of glandular tissue. KCNJ6: gene for potassium inwardly rectifying channels, subfamily J, member 6 (Kir3.2, GIRK2). This G channel is important for opioid receptor transmission and is involved in opioid effects on postsynaptic inhibition [34]. DRD4: dopamine receptor D4 belongs to the dopamine receptor D2-like family, which mediates reward and reinforcement effects (e.g., of heroin) [35].