Tramadol and psychiatric meds

[the5thelement]

It seems that tramadol has MAJOR drug interactions with all psychiatric drugs , eg. Reducing seizure threshold (lithium) , increasing risk of serotonin syndomre (SSRIs) and CNS depression with atypical antipsychotics. How do you deal with this? Is advising the patient to discuss with PCP about switching to another pain medication a viable strategy?

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[wolfvgang22]

This is a timely question, given that many physicians have turned to tramadol as a "safer" alternative to other opioids like hydrocodone, morphine, oxycodone, etc for patients with chronic pain due to the current concern about the opioid epidemic. Many, if not most, patients with chronic pain also have psychiatric illness like depression and anxiety. I know in the VA, nearly every patient I see is prescribed Tramadol. You are right to be concerned about the drug interactions.

I try to use the lowest effective doses of psychiatric medications and educate and warn the patient about possible interactions and adverse events, and document it carefully. Sometimes I have to tell a patient they need to discuss pain management options other than tramadol with the doctor managing their pain issues and I communicate this also to the doctor prescribing Tramadol. This may be ignored, met with frustration by the patient and prescriber, or the prescriber sometimes cuts the patient off Tramadol. Sometimes we offer patients dependent on opioids buprenorphine or suboxone, but I prefer pain management manage pain in that case, as the patient with chronic pain is often not abusing their prescribed opiates.

 

[nexus73]

I've seen a lot of patients on Tramadol plus SSRI with zero issues. I educate about risks and discuss symptoms of serotonin syndrome (most commonly patients will experience muscle twitching and hyper-reflexia early on so I tell them to watch for this and call if it occurs). I also check for it during visits. My understanding is severe serotonin syndrome occurs not so much from being on normal doses of multiple serotonergic meds, but when there is a large ingestion combined with a cytochrome inhibitor which skyrockets drug levels. For example, overdose on a month supply of Prozac plus a month of Wellbutrin: the Prozac increases serotonin and Wellbutrin inhibits the 2D6 pathway needed for Prozac so you end up with extremely high levels of serotonin reuptake blockade. I'm interested if the doctors who do a lot of inpatient consults, especially at academic/trauma centers, have other experiences.

The other common non-psych drugs besides Tramadol to be watchful for are Zofran and Flexeril with serotonin activity.

 

[SourceOfDenial]

Tramadol=tramadont

Between serotonergic activity, poor efficacy, hypoglycemia, hyponatremia, increased seizure risk, P450 interactions and the fact that it just sucks there is never a reason to prescribe it.

Codeine too, please go away.

The fear over low dose opioids versus tramadol is a total misunderstanding of opioid pharmacology.

 

[whopper]

I agree with all of the above.

There is data showing that Tramadol can help OCD sx because it's highly serotonergic. Problem though becomes what do you do long-term given the risk potential for addiction? Perhaps a bridge only med hoping an SSRI or SNRI could work later on but many of them don't. OCD is often times treatment-resistant.

I also sometimes wean people off of Buprenorphine using Tramadol. It's off-label. The problem is buprenorphine even at 0.25 mg daily for months still causes withdrawal when stopped that could last for weeks. The smallest pill it comes in is 2 mg so patients literally are cutting it down to 0.25 mg daily putting the pill under a magnifying glass and using an Xacto knife, and from there when we want to get them off I've been forced to try an in-between medication. I've tried Gabapentin high dosages with only partial success. I've also tried Lucemyra with decent success but insurance companies hardly ever pay for it.

So I tried Tramadol and so far have had great success but the sample size is very small (5). Surprisingly the conversion so far that seems to work for Buprenorphine 0.25 mg is well over 150 mg of Tramadol but from there we cut it down about 25-50 mg every 2-3 days and they end up weaning off of it in a few weeks. Yes I do find it extremely frustrating that the manufacturer doesn't provide Buprenorphine pills for dosages smaller than 2 mg, and I find it frustrating that insurance companies make it tough to get meds such as Lucemyra.

 

[SourceOfDenial]

I agree with all of the above.

There is data showing that Tramadol can help OCD sx because it's highly serotonergic. Problem though becomes what do you do long-term given the risk potential for addiction? Perhaps a bridge only med hoping an SSRI or SNRI could work later on but many of them don't. OCD is often times treatment-resistant.

I also sometimes wean people off of Buprenorphine using Tramadol. It's off-label. The problem is buprenorphine even at 0.25 mg daily for months still causes withdrawal when stopped that could last for weeks. The smallest pill it comes in is 2 mg so patients literally are cutting it down to 0.25 mg daily putting the pill under a magnifying glass and using an Xacto knife, and from there when we want to get them off I've been forced to try an in-between medication. I've tried Gabapentin high dosages with only partial success. I've also tried Lucemyra with decent success but insurance companies hardly ever pay for it.

So I tried Tramadol and so far have had great success but the sample size is very small (5). Surprisingly the conversion so far that seems to work for Buprenorphine 0.25 mg is well over 150 mg of Tramadol but from there we cut it down about 25-50 mg every 2-3 days and they end up weaning off of it in a few weeks. Yes I do find it extremely frustrating that the manufacturer doesn't provide Buprenorphine pills for dosages smaller than 2 mg, and I find it frustrating that insurance companies make it tough to get meds such as Lucemyra.

Have you tried going from 0.25mg suboxone film to butrans patch and taper? If you’re using stuff off label might as well go with bup.

 

[hebel]

Tramadol is more of an SNRI structurally, correct? I know research hasn't shown much, but any success using tramadol as monotherapy for depression/anxiety? Or just augmenting it with buspirone?

 

[whopper]

I've noticed it can have some help with anxiety and depression, the problem being is that there's a lack of a strong evidence base. The OCD thing I mentioned was in an article written by Paul Keck (basing this on memory, I don't have the time to litsearch it to give you a link). That all said what if it works? Problem is that it's a controlled substance and if the patient does feel better some of it might not be because of the serotonin but because they're possibly unintentionally abusing it.

 

[whopper]

Have you tried going from 0.25mg suboxone film to butrans patch and taper? If you’re using stuff off label might as well go with bup.

I've considered this route. Haven't tried it. If anyone has let me know your experiences.

 

[clausewitz2]

I've noticed it can have some help with anxiety and depression, the problem being is that there's a lack of a strong evidence base. The OCD thing I mentioned was in an article written by Paul Keck (basing this on memory, I don't have the time to litsearch it to give you a link). That all said what if it works? Problem is that it's a controlled substance and if the patient does feel better some of it might not be because of the serotonin but because they're possibly unintentionally abusing it.

The OCD tramadol evidence base appears to be mostly based on a couple of case reports from a single group, who just coincidentally have applied for a patent on the treatment process. There is also some strained reasoning from the fact that naloxone can make OCD sx worse transiently, therefore, handwave handwave opioid modulation. There is literally more evidence for using stimulants to treat OCD, and I don't recommend that either.

SNRIs are not that well-supported for OCD. Honestly if you are moving beyond an SSRI there is just no reason not to go to clomipramine (NOT any old TCA) first and foremost

 

[clausewitz2]

I've noticed it can have some help with anxiety and depression, the problem being is that there's a lack of a strong evidence base. The OCD thing I mentioned was in an article written by Paul Keck (basing this on memory, I don't have the time to litsearch it to give you a link). That all said what if it works? Problem is that it's a controlled substance and if the patient does feel better some of it might not be because of the serotonin but because they're possibly unintentionally abusing it.

See also: the robust support for low-dose buprenorphine for TRD. I strongly suspect serotonin is not the main driver.

 

[whopper]

The opioid angle treating the symptoms is food for thought considering that Buprenorphine as you mentioned could treat depression. I remember one of my first Buprenorphine patients became manic on it and I was thinking "WTF this has an antidepressant effect?" Remember this was years ago when Suboxone films just came out. Then just months later after getting some people off of Suboxone they'd come to my office telling me they were depressed being off of Suboxone despite never having MDD before.

 

[Splenda88]

Tramadol=tramadont

Between serotonergic activity, poor efficacy, hypoglycemia, hyponatremia, increased seizure risk, P450 interactions and the fact that it just sucks there is never a reason to prescribe it.

Codeine too, please go away.

The fear over low dose opioids versus tramadol is a total misunderstanding of opioid pharmacology.

PCP are scared to have the DEA in their doorstep...

 

[aim-agm]

The opioid angle treating the symptoms is food for thought considering that Buprenorphine as you mentioned could treat depression. I remember one of my first Buprenorphine patients became manic on it and I was thinking "WTF this has an antidepressant effect?" Remember this was years ago when Suboxone films just came out. Then just months later after getting some people off of Suboxone they'd come to my office telling me they were depressed being off of Suboxone despite never having MDD before.

Mu-opioid agonists have been known to treat depression since at least Aristotle. Medicine basically forgot about it when we developed serotenergic drugs, and the switch happened for safety reasons not efficacy ones.

 

[clausewitz2]

Mu-opioid agonists have been known to treat depression since at least Aristotle. Medicine basically forgot about it when we developed serotenergic drugs, and the switch happened for safety reasons not efficacy ones.

Yeah, standard of care for serious depression until iproniazid/isocarboxazid was morphine. Since MDD is not actually a natural kind and is an excessively broad trash can category, I wouldn't expect mu-opioid agonists to be effective in the long or even perhaps short term for everyone who's depressed, but I am willing to put good money on there being a subgroup who more or less have an intrinsic endorphin deficiency (whether in level, receptor polymorphism, aberrant connectivity, etc etc) that nothing else is going to do much for.

Alkermes had an NDA rejected last year for a buprenorphine/samidorphan investigational antidepressant for...a number of reasons, but one of the big ones was that their statistically significant results were driven by huge responses in a couple of patients. I understand the caution and I don't think it was necessarily the wrong decision (one of the panelists was quoted in the press as saying he voted no despite personally sometimes prescribing opioids to people with TRD) but I feel like I want to know a lot more about those two people who did really well with it. We should be studying them.

 

[aim-agm]

Yeah, standard of care for serious depression until iproniazid/isocarboxazid was morphine. Since MDD is not actually a natural kind and is an excessively broad trash can category, I wouldn't expect mu-opioid agonists to be effective in the long or even perhaps short term for everyone who's depressed, but I am willing to put good money on there being a subgroup who more or less have an intrinsic endorphin deficiency (whether in level, receptor polymorphism, aberrant connectivity, etc etc) that nothing else is going to do much for.

Alkermes had an NDA rejected last year for a buprenorphine/samidorphan investigational antidepressant for...a number of reasons, but one of the big ones was that their statistically significant results were driven by huge responses in a couple of patients. I understand the caution and I don't think it was necessarily the wrong decision (one of the panelists was quoted in the press as saying he voted no despite personally sometimes prescribing opioids to people with TRD) but I feel like I want to know a lot more about those two people who did really well with it. We should be studying them.

Read up on Tianeptine. Used for decades, well tolerated, about the same efficacy profile as TCAs (which is structurally is) even though it turned out to pretty much just be a mu-opioid agonist. Going by efficacy and safety, one could make the case that opioids should be first or second line for depression/anxiety...except for that pesky addiction potential.

Most depression responds well to mu-opioid agonists (see: ketamine). I don't know why, but I don't think there's an endorphin deficiency per se. My conjecture is that it has something to do with mu agonism ablating the "something is wrong" interpretation of the experiences leading to depression/anxiety in much the same way that it ablates a similar interpretation of noxious stimuli that leads to the experience of pain.

Samidorphan is basically an oral naloxone and the combination drug was meant to act at kappa but not at mu. It's failure provides evidence didn't work because mu is really where buprenoprhine's antidepressant activity is, although there may be a small subset of patient's where kappa is important.

 

[clausewitz2]

Read up on Tianeptine. Used for decades, well tolerated, about the same efficacy profile as TCAs (which is structurally is) even though it turned out to pretty much just be a mu-opioid agonist. Going by efficacy and safety, one could make the case that opioids should be first or second line for depression/anxiety...except for that pesky addiction potential.

Most depression responds well to mu-opioid agonists (see: ketamine). I don't know why, but I don't think there's an endorphin deficiency per se. My conjecture is that it has something to do with mu agonism ablating the "something is wrong" interpretation of the experiences leading to depression/anxiety in much the same way that it ablates a similar interpretation of noxious stimuli that leads to the experience of pain.

Samidorphan is basically an oral naloxone and the combination drug was meant to act at kappa but not at mu. It's failure provides evidence didn't work because mu is really where buprenoprhine's antidepressant activity is, although there may be a small subset of patient's where kappa is important.

I am very aware of tianeptine. It also turns out to have a lot of addiction potential although it's actually perfectly legal to buy without a prescription in the US. The kinds of folks who abuse research chemicals have known about it for a while. It's not clear that at doses usually prescribed it was actually doing much at opioid receptors (actually more activity as a promoter of serotonin reuptake) but your point is a good one.

I don't know that we can say that ketamine is acting primarily via mu-opioid action, although yes, I am aware of the naloxone co-administration studies. There have been replies since arguing that what naloxone also does is interfere with cAMP activity , which is plausibly the actual mechanism by which ketamine is useful as an antidepressant. This is supported by the abject failure of NMDA antagonists trying to copy ketamine as antidepressants but the to-date success of cAMP modulating compounds in animal models of depression. Adenosine generally as a target in depression is getting more attention (cf. observations and small trials with cilostazol and istradefylline) so this is definitely plausible as well.

You're right about combined drug ostensibly being a kappa opioid antagonist en toto, my point was just that I think that people who respond really well to manipulation of the endorphin system should be examined more closely.

 

[wolfvgang22]

I'm pretty sure tianeptine is schedule II, at least in Michigan.
Anyway, I would rather have access to Moclobomide than tianeptine because it is safer and offers a different mechanism of action for my patients who do not respond to our usual meds.

 

[sighchiatry]

I agree with all of the above.

There is data showing that Tramadol can help OCD sx because it's highly serotonergic. Problem though becomes what do you do long-term given the risk potential for addiction? Perhaps a bridge only med hoping an SSRI or SNRI could work later on but many of them don't. OCD is often times treatment-resistant.

I also sometimes wean people off of Buprenorphine using Tramadol. It's off-label. The problem is buprenorphine even at 0.25 mg daily for months still causes withdrawal when stopped that could last for weeks. The smallest pill it comes in is 2 mg so patients literally are cutting it down to 0.25 mg daily putting the pill under a magnifying glass and using an Xacto knife, and from there when we want to get them off I've been forced to try an in-between medication. I've tried Gabapentin high dosages with only partial success. I've also tried Lucemyra with decent success but insurance companies hardly ever pay for it.

So I tried Tramadol and so far have had great success but the sample size is very small (5). Surprisingly the conversion so far that seems to work for Buprenorphine 0.25 mg is well over 150 mg of Tramadol but from there we cut it down about 25-50 mg every 2-3 days and they end up weaning off of it in a few weeks. Yes I do find it extremely frustrating that the manufacturer doesn't provide Buprenorphine pills for dosages smaller than 2 mg, and I find it frustrating that insurance companies make it tough to get meds such as Lucemyra.

I use a compounding pharmacy for situations like this. They can suspend the medications in an oil base allowing you to adjust doses by sometimes as little as .025 mg.

 

[aim-agm]

I don't know that we can say that ketamine is acting primarily via mu-opioid action, although yes, I am aware of the naloxone co-administration studies. There have been replies since arguing that what naloxone also does is interfere with cAMP activity , which is plausibly the actual mechanism by which ketamine is useful as an antidepressant. This is supported by the abject failure of NMDA antagonists trying to copy ketamine as antidepressants but the to-date success of cAMP modulating compounds in animal models of depression. Adenosine generally as a target in depression is getting more attention (cf. observations and small trials with cilostazol and istradefylline) so this is definitely plausible as well.

Without getting too much into it, if a new agent which does a lot of things also happens to do the same thing as the prototypical treatment for a disease and the effects looks very similar to said prototypical treatment (including sharing aspects that are otherwise rare or unique), the null hypothesis is that it is that the "new" agent is acting through the already established mechanism. To date studies overall support the null hypothesis.

 

[clausewitz2]

Without getting too much into it, if a new agent which does a lot of things also happens to do the same thing as the prototypical treatment for a disease and the effects looks very similar to said prototypical treatment (including sharing aspects that are otherwise rare or unique), the null hypothesis is that it is that the "new" agent is acting through the already established mechanism. To date studies overall support the null hypothesis.

I really don't think depression (at least, DSM defined MDD) fits the disease model very well, but I am interested in what you propose the rate and unique aspects of opioid treatment for mood disorders that is shared by ketamine except "it's fast". I think the general point doesn't hold up that well in medicine, e.g. any bacterial disease where multiple antibiotics from different classes are effective. I would suggest the null hypothesis is actually "different molecules are different in a way reflected by divergences in their structure".

Naltrexone reduces alcohol cravings and binge drinking but that doesn't make alcohol an opioid.

 

[clausewitz2]

I'm pretty sure tianeptine is schedule II, at least in Michigan.
Anyway, I would rather have access to Moclobomide than tianeptine because it is safer and offers a different mechanism of action for my patients who do not respond to our usual meds.

Michigan is the only state this is true in. It is perfectly legal and unregulated by the FDA everywhere else in the US. It is in a strange situation like adrafinil (the prodrug of modafinil) where it does not have the legal status of a pharmaceutical here and thus can be purchased freely.

I mean moclobemide is fine and all but we still have access to the real, more effective thing in Parnate/Nardil/Marplan. I am 100% with you in wanting more mechanisms of action to offer though.

 

[wolfvgang22]

Michigan is the only state this is true in. It is perfectly legal and unregulated by the FDA everywhere else in the US. It is in a strange situation like adrafinil (the prodrug of modafinil) where it does not have the legal status of a pharmaceutical here and thus can be purchased freely.

I mean moclobemide is fine and all but we still have access to the real, more effective thing in Parnate/Nardil/Marplan. I am 100% with you in wanting more mechanisms of action to offer though.

Parnate isn't a reversible MAOI, unless I am mistaken.

 

[clausewitz2]

Parnate isn't a reversible MAOI, unless I am mistaken.

Certainly not. I meant more that theory, empirical evidence, and clinical experience suggest the irreversible MAOIs just work better and that moclobemide is a pale imitation. I get why it's an easier sell, but...y'know what, I'll dismount from that hobbyhorse.

 

[aim-agm]

I really don't think depression (at least, DSM defined MDD) fits the disease model very well, but I am interested in what you propose the rate and unique aspects of opioid treatment for mood disorders that is shared by ketamine except "it's fast". I think the general point doesn't hold up that well in medicine, e.g. any bacterial disease where multiple antibiotics from different classes are effective. I would suggest the null hypothesis is actually "different molecules are different in a way reflected by divergences in their structure".

Naltrexone reduces alcohol cravings and binge drinking but that doesn't make alcohol an opioid.

Briefly:
- IV administration results in temporary marked improvement and occasionally resolution of depression over hours
- However, PO administration results in antidepressant effects over weeks i.e. on the order of a hundred-fold difference in time to effect purely dependent on route of administration. (Tangentially, I haven't seen studies of explicit opioids other than PO and IV, but for ketamine only PO takes days/weeks. IV, IM, intranasal, transmucosal, etc. all act in hours.)
- Appears to have no antidepressant activity if patient in pain at time of administration
- More effective at treating suicidality than depression
- Efficacy ablated by naltrexone

 

[clausewitz2]

Briefly:
- IV administration results in temporary marked improvement and occasionally resolution of depression over hours
- However, PO administration results in antidepressant effects over weeks i.e. on the order of a hundred-fold difference in time to effect purely dependent on route of administration. (Tangentially, I haven't seen studies of explicit opioids other than PO and IV, but for ketamine only PO takes days/weeks. IV, IM, intranasal, transmucosal, etc. all act in hours.)
- Appears to have no antidepressant activity if patient in pain at time of administration
- More effective at treating suicidality than depression
- Efficacy ablated by naltrexone

Citation for pain entirely negating antidepressant/anti-suicidal effect? I had genuinely never heard of this so am very curious. I've yet to see any studies showing a convincing effect for oral ketamine but am willing to be open-minded. I am happy to believe the bit about suicidality and it is way more specific than "depressive symptoms" but does naltrexone really block the anti-suicidality effects?

I suppose I still think it's a stretch to conclude from those points alone that the only mechanism of action is one they have in common. I'm not saying you're necessarily wrong, I just think saying this is definitely established as proven fact is very premature.

 

[SourceOfDenial]

Citation for pain entirely negating antidepressant/anti-suicidal effect? I had genuinely never heard of this so am very curious. I've yet to see any studies showing a convincing effect for oral ketamine but am willing to be open-minded. I am happy to believe the bit about suicidality and it is way more specific than "depressive symptoms" but does naltrexone really block the anti-suicidality effects?

My own experience (and peers) with ketamine dissolving lozenges in the context of ketamine assisted psychotherapy has been quite profound, but very limited rigorous data out there. But as it uses the psychedelic assisted therapy model, hard to say what’s happening—drug effect or improves effectiveness of therapy?

 

[marj22]

I agree with all of the above.

There is data showing that Tramadol can help OCD sx because it's highly serotonergic. Problem though becomes what do you do long-term given the risk potential for addiction? Perhaps a bridge only med hoping an SSRI or SNRI could work later on but many of them don't. OCD is often times treatment-resistant.

I also sometimes wean people off of Buprenorphine using Tramadol. It's off-label. The problem is buprenorphine even at 0.25 mg daily for months still causes withdrawal when stopped that could last for weeks. The smallest pill it comes in is 2 mg so patients literally are cutting it down to 0.25 mg daily putting the pill under a magnifying glass and using an Xacto knife, and from there when we want to get them off I've been forced to try an in-between medication. I've tried Gabapentin high dosages with only partial success. I've also tried Lucemyra with decent success but insurance companies hardly ever pay for it.

So I tried Tramadol and so far have had great success but the sample size is very small (5). Surprisingly the conversion so far that seems to work for Buprenorphine 0.25 mg is well over 150 mg of Tramadol but from there we cut it down about 25-50 mg every 2-3 days and they end up weaning off of it in a few weeks. Yes I do find it extremely frustrating that the manufacturer doesn't provide Buprenorphine pills for dosages smaller than 2 mg, and I find it frustrating that insurance companies make it tough to get meds such as Lucemyra.

are you an addiction psychiatrist?

 

[Ceke2002]

It seems that tramadol has MAJOR drug interactions with all psychiatric drugs , eg. Reducing seizure threshold (lithium) , increasing risk of serotonin syndomre (SSRIs) and CNS depression with atypical antipsychotics. How do you deal with this? Is advising the patient to discuss with PCP about switching to another pain medication a viable strategy?

I'm a former psych patient, have been on Tramadol long term for neuropathy, and have been in emergency for serotonin syndrome (the priority 1 emergency kind of serotonin syndrome). The dosage combinations of Tramadol and Antidepressant to cause the SS was around 300mgs Tramadol daily, and a single 75mg dosage of Effexor. Because of this prior experience I obviously have to be careful with what medications I take, as I am still on Tramadol. So when my now former Psychiatrist wanted to try me on a different AD he thought might be more effective he started me out on a low dosage, booked me in for an extended appointment, had me take the first dose 20 minutes before arriving at the appointment, and then monitored me for the duration. The AD was Mirtazapine, and my understanding is that the risk of SS with that is much lower than other medications, but even so having me come in for 'medication monitoring' covered his backside and made me feel a lot safer as well. Not sure what your set up is, but maybe you could offer something similar for patients you feel might be at risk, but who aren't able or are unwilling to come off Tramadol and still need AD medication.