Recent advances in the use of opioids for cancer pain

Figures & data

Table 1 Weak and strong opioids commonly used in cancer pain

Opioid (route of administration)	Metabolic pathway	Metabolites	Main receptors	Bioavailability	Relative potency to oral morphinea	Specific comments
Weak opioid (Step 2 WHO analgesic ladder)
Codeine PO, PaR	Hepatic metabolism by cytochrome p450 (CYP2D6)	Norcodeine, morphine, Morphine-3-glucuronide (inactive) Morphine-6-glucuronide (active)	Mu-opioid receptor agonist	40% (variable)^Citation166	0.1	Prodrug of morphine. Up to 10% of Caucasians experience no analgesia from codeine because they are CYP2D6 poor metabolizers^Citation32
Tramadol PO, PaR	Hepatic metabolism via cytochrome p450 (CYP2D6)	O-desmethyltramadol (active)	Mu-opioid receptor agonist. Also action on adrenergic/serotonergic pathways	68%–100% (higher after multiple dosing due to saturation of first pass effect^Citation167	0.1–0.25 PO 0.1 PaR^Citation167	Risk of serotonin toxicity if used with other drugs which increase serotonin levels
Strong opioid (Step 3 WHO analgesic ladder)
Morphine PO, PaR, R	Hepatic metabolism by the enzyme UGT (UDP-glucuronosyltransferase)	Morphine-3-glucuronide (analgesically inactive) Morphine-6-glucuronide (analgesically active)^Citation168	Mu-opioid receptor agonist	20%–30% oral bioavailability^Citation169,Citation170		Morphine and its metabolites are excreted in the urine and accumulate in renal failure^Citation171,Citation172
Oxycodone PO, PaR, R	Hepatic metabolism by cytochrome p450 (CYP3A4 and 2D6)^Citation173,Citation174	Oxymorphone (active) but metabolites do not contribute to central action^Citation173	Mu-opioid receptor agonist Kappa-opioid receptor agonist (controversial)^Citation175,Citation176	60% oral bioavailability^Citation177	1.5–2.0^Citation178,Citation179	Reduced clearance in renal impairment^Citation180
Fentanyl PaR, TD, IN, TM	Metabolized in the liver	Inactive norfentanyl	Mu-opioid receptor agonist	Poor oral bioavailability due to high first-pass metabolism	70–100 when using TD fentanyl formulation^Citation181	Highly lipid soluble, taken up into fatty tissues. Less than 10% excreted unchanged in urine^Citation182
Methadone PO, R, PaR	Hepatic metabolism via cytochrome p450 (CYP 3A4)^Citation183	Inactive metabolites	Mu-opioid and delta-opioid receptor agonist. NMDA (N-methyl-D-aspartate) receptor antagonist. Amine reuptake inhibitor	80% oral bioavailability^Citation169	Considerable inter-individual variation in pharmacokinetics^Citation169,Citation184 influenced by dose^Citation185 and dosing schedule. Long plasma halflife, therefore higher potency ratio with repeated dosing	Highly protein bound.^Citation183 Fecal excretion.^Citation186 Safer in renal impairment
Buprenorphine PO, TD, TM	Hepatic metabolism via cytochrome p450 (CYP 3A4 and 2C8)	Norbuprenorphine	Partial mu-opioid receptor agonist. Kappa- and deltaopioid receptor antagonist Partial opioid-receptor-like 1 agonist	Poor oral bioavailability due to extensive first pass presystemic elimination^Citation187	100–115 when using TD buprenorphine formulation^Citation188^–^Citation190	Fecal excretion of buprenorphine.^Citation187 High receptor affinity therefore higher doses of naloxone are required to antagonize effects^Citation191
Hydromorphone PO, PaR, R	Hepatic metabolism	Hydromorphone-3-glucuronide (H-3-G)^Citation192 which is not analgesically active but is neuroexcitatory^Citation193	Mu-opioid receptor agonist	50%–60%^Citation194,Citation195	5–7.5^Citation196	H-3-G accumulates in renal failure^Citation197
Alfentanil PaR, IN	Hepatic metabolism via cytochrome p450 (CYP 3A4)^Citation198	Inactive metabolites	Mu-opioid receptor agonist		30	Rapid onset of action^Citation199 Short elimination half-life (90 minutes)^Citation200 Less than 1% excreted unchanged in urine.^Citation200 Safer in renal failure. Dose reduction in liver failure and elderly^Citation201

a For guidance only, as discussed in text.

Abbreviations: TM, transmucosal (buccal, sublingual); PO, oral; PaR, parenteral (SC/IV); TD, transdermal; R, rectal; IN, intranasal.

Table 2 Efficacy of opioid switching

Author	Type of study	Number of patients undergoing opioid switch	Successful outcome after opioid switching	Reason for switching	Comment
Mercadantea,^Citation16	Prospective uncontrolled study	118	87%	Uncontrolled pain 15.2% Adverse effects 28.8% Uncontrolled pain and adverse effects 50.8%	More than 1 opioid switch required in 7 patients (6%)
Riley^Citation18	Prospective case-controlled study	48	87%	Morphine responders compared to morphine non responders: Confusion and drowsiness (P = 5 × 10^−12) Pain relief (P = 2.4 × 10^−6) Nightmares (P = 5 × 10^−5) Nausea (P = 7.3 × 10^−3)	More than 1 opioid switch required in 4 patients (8.5%)
Wirz^Citation21	Prospective uncontrolled study	50	64%	Uncontrolled pain 60% Sedation 4% Itch 2% Gastrointestinal effects (nausea, constipation) 40%
Mercadante^Citation202	Prospective uncontrolled study	52	80%	Uncontrolled pain 20% Adverse effects 16% Uncontrolled pain and adverse effects 64%
Kloke*^Citation15	Retrospective uncontrolled study	103	65%	Uncontrolled pain 43% Adverse effects 20% Uncontrolled pain and adverse effects 15%
De Stoutz^Citation19	Retrospective uncontrolled study	80	73%	Uncontrolled pain 16% Cognitive failure 39% Hallucinations 24% Myoclonus 11% Nausea 9% Local irritation 1%	More than 1 opioid switch required in some patients

a Studies included changing from one opioid to another in order to improve pain and side-effect profile (ie, opioid switching) and also for other reasons (opioid rotation).

Table 3 Summary table of pharmacogenetics and response to morphine in human patients with cancer paina

SNP/s	Clinical response	Strongest P value	Method of phenotype definition	Type of study	Study population
Single gene effect
OPRM (mu-opioid receptor gene)
Main site of action for morphine and other opioids
OPRM A118G (rs1799971) and others	G allele associated with higher daily morphine dose required to achieve adequate pain control. No difference in side-effects scores	0.006	Total daily morphine dose. Average pain score, 11-point NRS (0–10). Side-effects scored on 4 point verbal rating score. Metabolites measured using liquid chromatography mass spectrometry	Prospective observational study. Single time point	99 cancer patients with controlled pain (average pain ≤4)^Citation47
OPRM A118G (rs1799971)	G allele associated with lower change in pain scores (NRS) between baseline and 7 days of morphine treatment	0.0001	5-point verbal rating scale and 11-point NRS (0–10). Change in NRS between baseline and 7 days of morphine treatment	Prospective observational study. Multiple time points with 8 week follow-up	137 patients starting morphine for cancer pain^Citation48
OPRM A118G (rs1799971)	G allele associated with higher daily morphine dose. No differences in pain scores	0.012	Total daily morphine dose. Average pain score, 11-point NRS (0–10)	Prospective observational study. Single time point	207 cancer patients on morphine^Citation49
OPRM A118G (rs1799971), rs589046 and others	Not associated with differences between morphine responder and non-responder	NS	Morphine responders were taking morphine for at least 1 month with good pain control and minimal side-effects Morphine non-responders had inadequate pain control and/or intolerable side-effects	Prospective observational study Single time point	186 cancer patients taking morphine^Citation203
COMT (Catechol-O-methyltransferase gene)
COMT codes for an enzyme which is involved in catecholamine metabolism
COMT Val158Met (rs4680) and others	>1 allele associated with differences between morphine responder and non-responder	0.003	Morphine responders were taking morphine for at least 1 month with good pain control and minimal side-effects. Morphine non-responders had inadequate pain control and/or intolerable side-effects	Prospective observational study. Single time point	228 cancer patients taking morphine^Citation204
COMT Val158Met (rs4680) and others	>1 allele associated with differences in central side-effects of drowsiness and confusion/hallucinations	0.003	Side-effects scored on a 4-point subjective categorical scale	Prospective observational study. Single time point	228 cancer patients taking morphine^Citation204
COMT Val158Met (rs4680)	Val allele associated with higher daily morphine dose requirements. No differences in serum morphine and metabolites and side-effect scores	0.025	Total daily morphine dose. Average pain score, 11-point NRS (0–10). Side-effects scored on 4-point verbal rating score. Metabolites measured using liquid chromatography mass spectrometry	Prospective observational study. Single time point	207 patients on morphine for cancer pain^Citation205
rs4818, COMT Val158Met (rs4680), rs6269, rs740603 and others (haplotype construction)	>1 haplotypes and alleles associated with differences in daily morphine dose requirements. No differences in serum morphine and metabolites and side-effect scores	0.006 (haplotype analysis)	Total daily morphine dose. Average pain score, 11-point NRS (0–10). Side-effects scored on 4-point verbal rating score. Metabolites measured using liquid chromatography mass spectrometry	Prospective observational study. Single time point	207 patients on morphine for cancer pain^Citation206
COMT Val158Met (rs4680)	Val allele associated with higher daily morphine dose requirements. No differences in pain scores	0.02	Total daily morphine dose. Average pain score, 11-point NRS (0–10)	Prospective observational study. Single time point	207 cancer patients on morphine^Citation49
MDR (Multi-Drug Resistance gene)
This gene codes for p-glycoprotein which is involved in drug transfer across the blood brain barrier
rs1128503, rs2032582, MDR C3435T (rs1045642) and others	>1 allele associated with differences in central side-effects of drowsiness and confusion/hallucinations	0.0003	Side-effects scored on a 4 point subjective categorical scale	Prospective observational study. Single time point	228 cancer patients taking morphine^Citation204
MDR1 C3435T (rs1045642)	C allele associated with lower change in pain scores (NRS) between baseline and 7 days of morphine treatment	0.001	5-point verbal rating scale and 11 point NRS (0–10). Change in NRS between baseline and 7 days of morphine treatment	Prospective observational study. Multiple time points with 8 week follow-up	137 patients starting morphine for cancer pain^Citation48
ARRB2 (B-arrestin-2)
This gene codes for a protein which is involved in intracellular receptor trafficking and degradation^Citation207,Citation208
T8662C (rs1045280), G11143A(rs2036657) and others	>1 allele associated with difference between morphine responder and non-responder	0.013	Morphine responders were taking morphine for at least 1 month with good pain control and minimal side-effects. Morphine non-responders had inadequate pain control and/or intolerable side-effects	Prospective observational study. Single time point	186 cancer patients taking morphine^Citation203
STAT6 (signal transducer and activator of transcription gene)
C-174T(rs167769), C9065T(rs841718) and others	T allele associated with differences between morphine responder and non-responder	0.026	Morphine responders were taking morphine for at least 1 month with good pain control and minimal side-effects. Morphine non-responders had inadequate pain control and/or intolerable side-effects	Prospective observational study. Single time point	186 cancer patients taking morphine^Citation203
UGT2B7 (UDP glycosyltransferase 2 gene). This enzyme is involved in the hepatic metabolism of morphine
A2098T(rs7438284), C2099T(rs7439366)	Not associated with differences between morphine responder and non-responder	NS	Morphine responders were taking morphine for at least 1 month with good pain control and minimal side-effects. Morphine non-responders had inadequate pain control and/or intolerable side-effects	Prospective observational study. Single time point	186 cancer patients taking morphine^Citation203
UGT2B7 H268Y and others	Not associated with differences in serum morphine and metabolite levels	NS	Metabolites measured using liquid chromatography mass spectrometry.	Prospective observational study Single time point	175 cancer patients taking morphine^Citation209
UGT1A1*28, UGT2B7 H268Y	Not associated with differences in serum morphine and metabolite levels	NS	Metabolites measured using liquid chromatography mass spectrometry.	Prospective observational study Single time point	70 cancer patients taking morphine^Citation210
Combined effect of >1 gene
OPRM/COMT
COMT Val158Met (rs4680) OPRM A118G (rs1799971)	OPRM AA/COMT Met/Met associated with lowest daily morphine dose requirements	0.012	Total daily morphine dose. Average pain score, 11-point NRS (0–10)	Prospective observational study. Single time point	207 cancer patients on morphine^Citation49
COMT/MDR
COMT Val158Met (rs4680), MDR C3435T (rs1045642) and others	Combination of COMT/MDR associated with reduced central side-effects of drowsiness and confusion/hallucinations	<0.0001	Side-effects scored on a 4-point subjective categorical scale	Prospective observational study. Single time point	228 cancer patients taking oral morphine. Morphine responders and non-responders^Citation204
OPRM/MDR1
OPRM A118G (rs1799971) MDR1 C3435T (rs1045642)	OPRM AA/MDR1 TT associated with greatest change in pain scores (NRS) between baseline and 7 days of morphine treatment	<0.00001	5-point verbal rating scale and 11-point NRS (0–10).	Prospective observational study. Multiple time points with 8 week follow-up	137 patients starting morphine for cancer pain^Citation48

a Studies involving >1 gene/clinical outcome are presented separately here. Only studies examining response to opioids for cancer pain are included here.

Abbreviations: NRS numeric rating scale; NS not significant.

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