Interaction
ALL OPIOIDS: a) As a CNS depressant, paroxetine has the potential to enhance the adverse or toxic effects of other CNS depressants such as opioids.
CODEINE: Codeine may not provide effective analgesia when taken in combination with paroxetine.
DEXTROMETHORPHAN: a) Inhibition of dextromethorphan metabolism by paroxetine is well established.
b) Two case reports describe patients developing serotonin syndrome after taking paroxetine and dextromethorphan together.
FENTANYL: 3 case reports describes patients taking paroxetine who experienced serotonin syndrome or toxicity after starting fentanyl. Symptoms resolved when both medications were stopped.
HYDROCODONE: Maximum plasma concentration, half-life, and AUC of hydrocodone was not altered by paroxetine.
Maximum plasma concentration and AUC of hydromorphone (minor active metabolite) was decreased.
HYDROMORPHONE: An 81 year old woman who took related drug fluoxetine 20 mg daily and other medications for several years developed abnormal movements, confusion, incoherent speech, sweating, redness, tremor, hyperreflexia and muscle spasm 2 days after starting hydromorphone 12 mg daily. Fluoxetine was stopped and the symptoms resolved.
LOPERAMIDE: QTc prolongation has been observed with paroxetine. Concomitant use with high-dose loperamide (>100 mg/day) may result in an arrhythmia with the potential to develop Torsades de Pointes.
MEPERIDINE: a) A case report describes a 44 year old woman taking related drug citalopram 20 mg daily increased to 40 mg daily, transdermal fentanyl, IV hydromorphone or oral hydrocodone/acetaminophen PRN, promethazine, gatifloxacin, zolpidem, and lansoprazole developed symptoms of serotonin syndrome within 10 hours of starting meperidine PRN via patient controlled analgesia (PCA). The total dose of meperidine was 230 mg over 8 hours. Meperidine was stopped and the symptoms resolved.
METHADONE: a) Methadone may decrease the metabolism of paroxetine.
b) In a study of 10 patients with narcotic dependence receiving methadone maintenance therapy (8 extensive CYP2D6 metabolizers and 2 poor CYP2D6 metabolizers), co-administration of paroxetine 20 mg resulted in a 35% increase in steady-state methadone levels. In extensive metabolizers, both R- and S-methadone levels increased, but only S-methadone levels increased in poor metabolizers. With the exception of one patient reporting feeling high the first night after paroxetine initiation, no symptoms of toxicity or over-medication were reported.
c) QTc interval prolongation has been observed with paroxetine, thus concomitant use with methadone may result in an arrhythmia with the potential to develop Torsades de Pointes.
MORPHINE:A patient, who had been taking paroxetine prior to surgery, was given morphine and ondansetron during the surgery. She experienced post-operative delirium (agitation, confusion, uncontrolled limb movements, abnormal ocular function, hypertension, pyrexia, brisk reflexes, ankle clonus, elevated creatinine phosphokinase (CPK)) during the following 2 days.
OXYCODONE: a) 20 CYP2D6 extensive or ultrarapid metabolizers taking oxycodone were given paroxetine 20 mg daily for 7 days. The AUC of oxycodone was increased by 19%. The AUC of the metabolite noroxycodone was increased 2-fold, while the AUC of the metabolite oxymorphone was decreased by 67%. Use of rescue analgesia or oxycodone efficacy was not altered. 2 placebo controlled studies showed that paroxetine decreased the AUC of oxymorphone by 44-66% and increased the AUC of noroxycodone by 68-70% but had no effect on pain scores.
b)12 healthy subjects given paroxetine 20 mg daily for 3 doses had no change in the pharmacokinetics of a single dose of oxycodone or noroxycodone, but the maximum concentration of oxymorphone was decreased by 38%. Unlike the other studies, in this study pre-treatment with paroxetine decreased miosis and oxycodone analgesia.
c) Symptoms of serotonin syndrome occurred in a patient taking related drug escitalopram and extended release oxycodone after the oxycodone dose was increased.
TRAMADOL: a) A potential risk for serotonin syndrome exists due to tramadol also causing blockade of serotonin reuptake. In addition, an increase in seizure risk was noted by the manufacturer of tramadol when used with SSRIs.
b) A man taking paroxetine 20 mg daily developed symptoms of serotonin syndrome (shivering, diaphoresis, myoclonus) and became subcomatose 12 hours after receiving a 100 mg dose of tramadol. Tramadol was discontinued and his paroxetine dose was reduced by 50%; symptoms resolved over the following week.
c) 3 days after initiating tramadol 50 mg three times daily, a 78-year-old woman taking paroxetine 20 mg daily developed nausea, diaphoresis, and irritability. Her condition worsened the following day and she developed muscular weakness, confusion, pyrexia, and tachycardia. Both drugs were withdrawn and her symptoms resolved. Paroxetine was later restarted with no problems.
d) A similar interaction was seen in another elderly woman, taking paroxetine 10 mg daily, 2 days after tramadol 50 mg four times daily was initiated.
e) 56 days after starting treatment with tramadol, paroxetine, and doxepin, a patient with tetraparesis and chronic pain experienced nightmares and hallucinations. Symptoms resolved only after discontinuation of medications.
f) In a placebo-controlled study of 16 healthy subjects pre-treated with paroxetine 20 mg daily for 3 days, investigators saw a 35% increase in tramadol AUC and a 40-67% decrease in the AUC of the O-demethylated metabolites. The analgesic effect of tramadol was also diminished. Another study found a similar, dose-dependent reduction in the production of (+)-O-desmethyltramadol when patients were given tramadol and paroxetine.
g) A 53-year-old patient developed serotonin syndrome and mania dung treatment with paroxetine and tramadol. This patient decided to increase the paroxetine and tramadol dosage to four tablets per day due to worsening pain. The manic symptoms persisted even after the resolution of the other symptoms of serotonin syndrome after one week.
OTHER OPIOIDS: a) The serotonergic effects of SSRIs may be enhanced by concomitant use with serotonergic opioids.
b) Concomitant use of paroxetine and opioids increase patient risk of secondary constipation, potentially leading to hemorrhoids, rectal prolapse, and fecal impaction.
Mechanism
ALL OPIOIDS: a) The exact mechanism of increased CNS depression is unknown, but it appears that the effects are mainly additive.
CODEINE: Reduced codeine efficacy is due to reduced formation of the active metabolite opioid agonist (morphine) via CYP2D6 due to strong CYP2D6 inhibition by paroxetine.
DEXTROMETHORPHAN: a) Paroxetine inhibits CYP2D6 which metabolizes dextromethorphan.
b) Serotonin syndrome is a dose-related response to the use of serotonergic drugs, often in combination. Genetic polymorphism in CYP2D6 function leads to differences in the ability to metabolize dextromethorphan which may explain the differences in clinical experiences reported by those who abuse dextromethorphan for its dissociative effects.
FENTANYL, HYDROMORPHONE, MEPERIDINE: Additive serotonergic effects could contribute to an increased risk of serotonin syndrome.
LOPERAMIDE: Both paroxetine and high dose loperamide can cause QTc interval prolongation. When used together, these effects may be additive.
METHADONE: a) Both methadone and paroxetine have been identified as a moderate inhibitors of the CYP2D6 enzymatic pathway. Paroxetine is also a CYP2D6 substrate.
c) Paroxetine and methadone are both QTc prolonging agents.
OXYCODONE: Paroxetine inhibits CYP2D6 which reduces metabolism of oxycodone to oxymorphone.
TRAMADOL: a) Additive serotonergic effects could contribute to an increased risk of serotonin syndrome.
Tramadol can cause seizures, and SSRIs can lower the seizure threshold.
Paroxetine is a strong CYP2D6 inhibitor. This can lead to decreased metabolism of tramadol to the active metabolite with analgesic activity.
Paroxetine is also a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 and this may explain the differences seen between poor and extensive metabolizers.
OTHER OPIOIDS:a) Additive serotonergic effects.
b) Decreased smooth-muscle contractility through paroxetine anticholinergic effects, combined with reduced peristalsis, increased anal sphincter tone, and reduced defecation response through stimulation of mu and delta opioid receptors.
Significance
ALL OPIOIDS: a) It is important to warn patients of the potential for a reduction in psychomotor function when these drugs are taken concurrently. They may or may not be aware of their deterioration in skill level and response will vary between individuals. They will likely experience a deterioration in their abilities to operate a vehicle and/or carry out tasks that require mental alertness.
CODEINE: Codeine may not be the best choice for analgesic therapy in patients currently maintained on paroxetine due to its potential to reduce the analgesic effect of codeine.
DEXTROMETHORPHAN: a) This interaction appears to affect extensive CYP2D6 metabolizers (the most common phenotype) only.
b) If therapeutic doses of dextromethorphan and an SSRI are enough to elicit serotonin syndrome, then the combination of these drugs should be avoided. One case study suggests that supra-therapeutic doses of dextromethorphan are a risk factor for the development of serotonin syndrome.
HYDROCODONE: Hydrocodone can be administered with paroxetine without dose modification.
LOPERAMIDE:Due to increased risk of QTc interval prolongation, it is recommended to avoid concomitant use of high-dose loperamide (>100 mg/day) and paroxetine.
METHADONE: a,b) Although co-administration of paroxetine and methadone does not appear to result in increased toxicity, caution is advised as information regarding this interaction is limited. Patients should be monitored during any dosage adjustments.
c) Due to increased risk of QTc interval prolongation, caution is recommended with concomitant use of methadone and paroxetine.
OXYCODONE: Overall, analgesic efficacy of oxycodone was not generally reduced by paroxetine.
TRAMADOL: Tramadol may not be the best choice for analgesic therapy in patients currently maintained on paroxetine due to the potential for paroxetine to reduce the analgesic effects of tramadol, and increased risk of serotonin syndrome.
Caution with concomitant use of tramadol and SSRIs is recommended in patients who are already at increased risk for seizures.
OTHER OPIOIDS: a)While there is potential for increased risk of serotonin syndrome-like symptoms with the concomitant use of SSRIs and opioids, it appears to be relatively rare. Little evidence exists to suggests a contraindication to concomitant use; however, it is recommended to monitor for serotonin syndrome if used in patients with altered mental status, autonomic dysfunction, or those experiencing neuromuscular adverse effects.
b) Encourage patients to exercise regularly (ideally 30-60 minutes of aerobic exercise at least 5 times weekly) if possible, maintain a fibre intake of 25-30 grams/day, and not ignore the urge to defecate. Supplementary use of laxatives such as PEG 3350 may be necessary if it has been more than 3 days since they have had a bowel movement, or if constipation has become a chronic condition. Attempt to use the lowest effective dose of each agent to minimize this adverse effect.
Serious Risk for Harm
ALL OPIOIDS: Paroxetine can cause sleepiness, dizziness and confusion. Opioid use can make this worse, and make it more dangerous to drive or do activities that require alertness and attention.
Serious Risk for Harm
DEXTROMETHORPHAN: When high doses of dextromethorphan are combined with paroxetine, you could get: very high fever, really sick, dangerously high blood pressure, heart problems and even die. This is 'serotonin syndrome'.
Paroxetine can slow down the removal of dextromethorphan from your body. This could give you more side effects or put you at risk of serotonin syndrome (described above).
FENTANYL: When combined with paroxetine, you could get: very high fever, really sick, dangerously high blood pressure, heart problems and even die. This is 'serotonin syndrome'.
HYDROMORPHONE: When combined with paroxetine, you could get: very high fever, really sick, dangerously high blood pressure, heart problems and even die. This is 'serotonin syndrome'.
LOPERAMIDE:Use of both paroxetine and very high doses of loperamide (more than 100 mg in one day) can cause abnormal heart rhythm. Mixing these two medications could make the chance of having a deadly abnormal heart beat more likely, so this cocktail should be avoided.
MEPERIDINE: When combined with paroxetine, you could get: very high fever, really sick, dangerously high blood pressure, heart problems and even die. This is 'serotonin syndrome'.
METHADONE: a) Methadone can slow down the removal of paroxetine from your body. This would be like taking extra paroxetine, and could cause more side effects.
b) Methadone and paroxetine can both affect heart rhythm. When methadone is combined with paroxetine, it could lead to a severe abnormal heart rhythm that is very dangerous and can even cause death.
MORPHINE: When combined with paroxetine, you could get: very high fever, really sick, dangerously high blood pressure, heart problems and even die. This is 'serotonin syndrome'.
OXYCODONE: When combined with paroxetine, oxycodone is less effective for pain, and you could get: very high fever, really sick, dangerously high blood pressure, heart problems and even die. This is 'serotonin syndrome'.
TRAMADOL: When combined with paroxetine, tramadol is less effective for pain, and you could get: very high fever, really sick, dangerously high blood pressure, heart problems and even die. This is 'serotonin syndrome'.
If you have epilepsy taking tramadol with paroxetine could make you have seizures more often.
Think First
CODEINE: Painkillers with codeine may not work as well as expected when you are taking paroxetine.
ALL OPIOIDS: Taking paroxetine can make you constipated. Opioids can make this worse. To help keep your bowels moving properly, try to exercise for 30 to 60 minutes 5 times a week, eat high fibre foods (for example, whole grains and fruits like bananas and kiwi fruit), and don’t “hold it in” when you need to use the washroom.
See your pharmacist, nurse or doctor for advice about laxatives if constipation becomes problematic for you (for example, pain with bowel movements or more than 3 days between bowel movements).