Table 2.
Overview of included publications reporting drug–drug interactions (DDIs) involving opioids used for pain treatment in cancer patients
| Author (year) | Study design (number of patients) | Patients | Primary treatment (dose, route of administration) | Coadministered drug (dose, route of administration) | Clinical presentation | Underlying mechanism as proposed by the authors | Additional information provided by the authors of the included papers and the present review |
|---|---|---|---|---|---|---|---|
| Tramadol | |||||||
| Huang et al10 (2007) | Case report | 39-year-old woman with lymphoma | IV tramadol (150 mg/day) | Pethidine (25 mg injection) | Confusion with agitation and visual hallucinations 2 hours after pethidine injection, followed by catatonia with mutism and immobile standing, for 2 days | Anticholinergic and serotonergic effects; imbalance between cholinergic and dopaminergic systems in the CNS | Other drugs (pantoprazole, cyclophosphamide, prednisolone) could have contributed to the symptoms |
| Dextropropoxyphene/propoxyphene | |||||||
| Yu et al11 (1986) | Case series (one patient) | 69-year-old woman with myelofibrosis | Carbamazepine (600 mg/day) | Dextro-propoxyphene (32 mg q4h) | Drowsiness progressing to coma on the fifth day of the co-treatment | Inhibition of carbamazepine metabolism | Two other cases of patients with nonmalignant diseases are also reported |
| Oles et al12 (1989) | Case series (two patients) | Two patients; 60-year-old man and 23-year-old woman with brain tumors | Carbamazepine (~9–23 mg/kg/day) | Propoxyphene | Lightheadedness, blurred vision, double/triple vision, ataxia, nausea and vomiting after 2–3 days of co-treatment | Inhibition of carbamazepine metabolism (CYP450) | Six other cases of patients with nonmalignant diseases are also reported |
| Tapentadol | |||||||
| Sanders13 (2013) | Case report | 58-year-old woman with endometrial carcinoma | PO clonidine (400 mg/day) | PO tapentadol (50 mg per dose) | Blood pressure increase within 24 hours after tapentadol initiation. Similar episode 2 hours after tapentadol was resumed | Inhibition of norepinephrine reuptake | |
| Morphine | |||||||
| Potter et al14 (1989) | Case series (seven patients) | Nineteen patients; ten men and nine women aged 34–75; with malignant disease, and high dose of morphine or morphine-related side effects | PO morphine (120–1,200 mg/day), SC morphine (210–800 mg/day) | Antidepressants (TCA), antipsychotics (phenothiazines and haloperidol), antiemetics, NSAIDs | Side effects in 13 of the 19 patients (myoclonus in 12, and hyperalgesia in 1). Antidepressants and antipsychotics were used only in patients with side effects (7/13). A greater proportion of patients with side effects used thiethylperazine and NSAIDs | Antagonistic effect on dopamine receptors (phenothiazines); inhibition of catecholamines release (NSAIDs); promotion of proconvulsant properties of opioids | Abnormal concentrations of electrolytes in some patients could have contributed to the symptoms |
| Smith and Guly15 (2004) | Case report | 60-year-old woman with metastatic renal cell carcinoma | SR morphine (90 mg q12h) | IV nalbuphine (30 mg) | Symptoms of opioid withdrawal, resistance to additional doses of intravenous morphine | Antagonistic effect on mu opioid receptors | |
| Hartree16 (2005) | Case series (one patient) | 49-year-old man with metastatic prostate cancer | SR morphine (360 mg q12h) | IM nalbuphine (10 mg) | Increased pain and symptoms of opioid withdrawal | Antagonistic effect on mu opioid receptors | Another patient (treated with methadone and nalbuphine) is reported below |
| Ripamonti et al17 (1998) | Case series (three patients) | Three patients; one man and two women aged 20–58; with sarcomas and cervical carcinoma | PO, SC, spinal morphine (in increasing doses; 20–2,000 mg MEDD) | SC or IV somatostatin (3 mg) | Increased pain, difficulty in controlling pain | Opioid antagonistic properties of somatostatin | One patient initially on oral methadone with poor analgesic effect, switched to morphine |
| Piquet et al18 (1998) | Case series (one patient) | 72-year-old man with metastatic bladder carcinoma | IT morphine (10 mg) | IT bupivacaine (7.5 mg) with epinephrine | Coma and respiratory depression 10 minutes after IT injection of morphine and bupivacaine (morphine was resumed in the same dose after 4 days) | Inhibition of the stimulating effect of pain on respiration | A case of a patient with nonmalignant disease is also reported |
| Upadhyay et al19 (2008) | Case report | 80-year-old man with metastatic lung cancer | PO morphine (dose increased from 15 mg to 30 mg q4h) | PO amitriptyline (dose increased from 25 mg/day to 50 mg/day), ranitidine (300 mg/day) | Deep and prolonged sedation, not responding to painful stimuli with respiratory rate eight per minute during titration rate of the analgesic dose | Sedating effect of amitriptyline; inhibition of morphine metabolism (amitryptyline and ranitidine) | Patient with hypoalbuminemia |
| Martinez-Abad et al20 (1988) | Case report | 42-year-old man with cancer of the larynx | IV ranitidine (150 mg q8h) | IV morphine (50 mg/day) | Three episodes of confusion with agitation after three subsequent doses of ranitidine during morphine infusion | Mechanism not clear (according to the authors) | Inhibition of morphine metabolism by ranitidine has been demonstrated45,46 |
| Guo et al21 (2006) | Case report | 18-year-old woman with nasopharyngeal carcinoma | IM haloperidol (4 mg/day), IV morphine (up tô10 mg/h) and ED injection of morphine (2 mg) | IV naloxone (3 injections of 0.1–0.2 mg at 30-minute intervals) | Three episodes of extrapyramidal symptoms (restlessness, torticollis, oculogyric response) 5 minutes after each naloxone injection | Reversal of opioid-related protection from haloperidol-induced extrapyramidal side effects | |
| Bortolussi et al22 (1994) | Case series (four patients) | Four patients; three men and one woman aged 53–56; with metastatic renal cell carcinoma | SR morphine | IV recombinant interleukin-2 (rIL-2) | Coma and/or respiratory depression | Toxic synergy on CNS; accumulation of morphine metabolites due to acute renal failure (induced by rIL-2) | |
| Hydromorphone | |||||||
| Fainsinger et al23 (1993) | Case report | 85-year-old woman with breast cancer | PO hydromorphone (24 mg q4h, 12 mg prn) | Captopril (50 mg/day) | Confusion with agitation and hallucinations, after a few days of co-treatment | Accumulation of hydromorphone metabolites due to renal failure (induced by captopril) | |
| Oxycodone | |||||||
| Watanabe et al24 (2011) | Case series (seven patients) | Nine patients; two men and seven women aged 39–82; with maxillary tumor or hematologic malignancies | PO oxycodone (~0.2–2.0 mg/kg/day) | PO or IV voriconazole (~2.2–8.0 mg/kg/day) coadministered or discontinued | Adverse events (vomiting, drowsiness, hypopnea, delirium, sweating, hypotension, uncontrolled pain) in seven of nine patients; after 1–10 days of co-treatment | Inhibition of CYP3A4 | Commented in Hagelberg et al42 |
| Walter et al25 (2012) | Case report | 77-year-old woman with lung cancer | SR oxycodone (50 mg q12h), IR oxycodone (5 mg prn) | Citalopram (20 mg/day) | Tremor, weakness, inability to coordinate motor movements, confusion (serotonin syndrome). The symptoms resolved within 48 hours after oxycodone was changed to morphine | Hyperstimulation of central 5-HT1A and 2A receptors (citalopram); disinhibition of serotonergic neuronal activity by suppressing GABA-mediated inhibition (oxycodone) | The patient also used esomeprazole, which could have inhibited citalopram clearance |
| Rosebraugh et al26 (2001) | Case report | 34-year-old man with lymphoma | PO sertraline (50 mg/day) | PO oxycodone (200 mg over 48 hours) | Severe tremor and visual hallucinations (probable serotonin syndrome). The symptoms resolved within 12 hours after sertraline was stopped and cyproheptadine administered | Hyperstimulation of central 5-HT1A and 2A receptors (sertraline); disinhibition of neuronal activity by suppressing GABA-mediated inhibition (oxycodone) | |
| Fentanyl | |||||||
| Takane et al27 (2005) | Case report | 61-year-old man with parotid gland adenocarcinoma | TD fentanyl (dose increased from 2.5 mg to 7.5 mg; every 3 days) | PO rifampin (300 mg/day) | Severe pain after rifampin initiation. Patient continued to have pain despite three-fold increase in fentanyl dose | Induction of CYP3A4 | The ratio of serum fentanyl concentration/dose decreased to 20%–50% of baseline value |
| Morii et al28 (2007) | Case report | 64-year-old man with colon cancer | Rifampicin (450 mg/day) | TD fentanyl (dose increased from 0.6 mg/day to 2.5 mg/day) | Poor analgesia | Induction of CYP3A4 | |
| Mercadante et al29 (2002) | Case report | 67-year-old man with head and neck cancer | TD fentanyl (50 µg/h) | PO itraconazole (400 mg/day) | Agitated delirium with myoclonus 24 hours after starting itraconazole | Inhibition of CYP3A4 | Patient also used omeprazole and ibuprofen, which could have contributed to the event (by inhibition of fentanyl metabolism and renal excretion) |
| Hallberg et al30 (2006) | Case report | 46-year-old man with tonsillar cancer | TD fentanyl (150 µg/h) | PO fluconazole (50 mg/day) | Death after 3 days of co-treatment | Inhibition of CYP3A4 | Postmortem blood analysis showed toxic concentration of fentanyl. Patient used also other drugs that could have contributed to the event (morphine, oxazepam, zolpidem) |
| Levin et al31 (2010) | Case report | 85-year-old man with lung cancer | IV fentanyl (25 µg/h) | Diltiazem | Hypoactive delirium, somnolence, miosis after 3 days of coadministration | Inhibition of CYP3A4 | Patient with chronic renal insufficiency |
| Cronnolly and Pegrum32 (2012) | Case report | 72-year-old woman with metastatic breast cancer | TD fentanyl (87 µg/h) | PO clarithromycin (1 g/day) | Coma and respiratory depression 2 days after clarithromycin initiation | Inhibition of CYP3A4 | Patient with kidney disease on hemodialysis |
| Tsutsumi et al33 (2006) | Case report | 47-year-old woman with leukemia | TD fentanyl (25 µg/h), discontinued | Cyclosporine | Opioid withdrawal syndrome 1 day following fentanyl cessation. Symptoms disappeared after fentanyl was resumed | Inhibition of CYP3A4 | |
| Morita et al34 (2004) | Case report | 67-year-old man with esophageal cancer | IV fentanyl (500 µg/day) | IV haloperidol (2.5–7.5 mg/day) | Worsening of pre-existing delirium (days 3–6). On day 7 muscle rigidity, fever, severe diaphoresis, tachycardia, hypertension, tachypnea, and coma (neuroleptic malignant syndrome) | Antagonistic effect on dopamine receptors (haloperidol); modification of dopamine metabolism in the CNS (fentanyl) | Hypocalcemia, hypophosphatemia and hypomagnesemia in this patient could have contributed to the symptoms |
| Ailawadhi et al35 (2007) | Case report | 65-year-old woman with myeloproliferative disease | Citalopram | TD fentanyl (25 µg/h) | Confusion, agitation, tremors, hyperreflexia, myoclonus, unsteady gait, tachycardia (serotonin syndrome) within 24 hours of fentanyl initiation. The symptoms resolved within 24–36 hours after fentanyl was replaced by oxycodone | Overstimulation of serotonin receptors (citalopram); inhibition of serotonin reuptake and increase of serotonin release in the CNS (fentanyl) | |
| Buprenorphine | |||||||
| Moro et al36 (2006) | Case report | 34-year-old man with metastatic osteosarcoma | Ifosfamide (2 g/m2/day for 3 days) | TD buprenorphine (35–52.5 µg/h) | Confusion, miosis, respiratory depression and bradycardia within 36 hours of the co-treatment | Inhibition of CYP3A4 (due to saturation of the enzyme by ifosfamide) | Commented by Davis (best interpretation for the event was rapid increase in buprenorphine dose)43 |
| Methadone | |||||||
| Hartree16 (2005) | Case series (one patient) | 54-year-old man with rectal carcinoma | PO methadone (20 mg/day) | IM nalbuphine (10 mg) | Increased pain and symptoms of opioid withdrawal | Antagonistic effect on mu opioid receptors | Another patient (treated with morphine and nalbuphine) is reported above |
| Benítez-Rosario et al37 (2006) | Case report | 61-year-old woman with metastatic lung cancer | PO methadone (210 mg/day) | Carbamazepine (1,200 mg/day), discontinued | Loss of consciousness and respiratory depression eleven days after carbamazepine discontinuation | Disappearance of carbamazepine inducing effect on metabolizing enzymes | The dose of methadone was increased within a week before the incident |
| Tarumi et al38 (2002) | Case report | 60-year-old man with gastric cancer | PO methadone (45–75 mg/day) | IV fluconazole (100 mg/day) | Unresponsiveness and respiratory depression 4 days after fluconazole initiation | Inhibition of CYP3A4 and 2C9 | Patient also used omeprazole, which could have contributed to the accumulation of methadone (by inhibition of CYP2C19 and CYP3A4) |
| Sorkin and Ogawa39 (1983) | Case report | 76-year-old man with metastatic lung cancer | PO methadone (5 mg q8h), SC morphine (8 mg prn) | IV cimetidine (1.2 g/day) | Respiratory depression 6 days after cimetidine initiation, 3 h after the rescue dose of morphine | Inhibition of liver enzymes | Cimetidine is a weak CYP3A4 inhibitor44 |
| Elsayem and Bruera40 (2005) | Case report | 70-year-old man with gastric cancer | Methadone (10 mg q8h, 2 mg prn) | Sertraline (100 mg/day) | Coma and respiratory depression 3 days after sertraline dose was increased from 50 mg/day to 100 mg/day | Inhibition of CYP3A4 | Severely malnourished patient with a history of alcoholism |
| Walker et al41 (2003) | Case series (one patient) | 61-year-old woman with rectal cancer | PO methadone (600–700 mg/day) | Sertraline (50 mg/day), midazolam, IV fentanyl (prn) | Two episodes of ventricular tachycardia (torsades de pointes) | Interference with methadone metabolism (sertraline, midazolam, and fentanyl, substrates of CYP3A4); increase in methadone blood levels | High dose of methadone and preexisting cardiac disease in the patient Two other cases of patients with nonmalignant disease are also reported |
Abbreviations: PO, oral; IR, immediate release; SR, slow release; SC, subcutaneous; IV, intravenous; TD, transdermal; ED, epidural; IT, intrathecal; q4h, every four hours; q12h, every 12 hours; prn, as required; MEDD, morphine equivalent daily dose; NSAIDs, nonsteroidal anti-inflammatory drugs; TCA, tricyclic antidepressants; CNS, central nervous system; BP, blood pressure.