The benzodiazepines and zolpidem are fine if used as a p.r.n., but I find most patients at some point end up having weeks or months require p.r.n.'s, after which they are dependent on these drugs.
Alternative, all off label, include trazadone, gabapentin, mirtazapine, quetiapine...and most recently Lyrica...
What evidence is there for ANY of the above and, since it is "new kid on the block," Lyrica???
Dear Lewis,
It is very important clinical question. In my daily work i suggest to psychiatrists and GPs to introduce Lyrica, especially in patients with polypharmacy and addiction to benzodiazepines. I will put my opinion:
+ for LYRICA
- no need for benzodiazepines and antipsychotics (quetiapine is used often for this purpose in Europe)
- no extra drug-drug interactions (Lyrica has this positive effect)
- no problem with liver injuries and enzymes inductions (especially appropriate in patients with long term addiction)
- mild effect (SMD=0,5-0,6) for general anxiety disorder, which is usually present in psychiatric patients
- pain comorbidity and diabetes and seizures
- no fast up and down regulation of receptors (mechanism of action), which is seen after the tolerance is established in patients treated on quetiapine
- no metabolic ADE, which is usually seen in H1 blockers (e. g. mirtazapine, quetipine)
- different mechanism of action (no GABA action (few), no H1 action)
- for LYRICA
- relative few data on positive effect (however there are few drugs which have positive effects on sleeping but are used often, e. g. quetiepine).
- high sedative effect, which is dose dependent usually
- bad adherence on drug (many capsules per day)
- kidney failure and dosage adjustment
- problem in switching in bipolar disorder (especially mania, which is less often seen in Neurontin)
- expensive drug
If I sum up Lyrica can reduce polypharmacy, because the number of drugs can be reduced by adding Lyrica, because drug has multiple indications. As clinical pharmacist specialist from psychiatry I often suggest Lyrica.
Regards,
Matej
There is little *evidence* (in the sense of RCTs etc) on pregabalin ("Lyrica") and insomnia. However, there is an avalanche of anecdotal reports that it is helpful with anxiety-induced insomnia (the preponderance of insomnia). Like BZDs, it upregulates GABA, but as Matej suggests above it does so much more "gently" and has a longer half-life than most BZDs. Clinicians I have spoken with often refer to it as a "much stronger version of gabapentin". Like trazadone and mirtazapine, pregabalin has antidepressant effects as well, but I think for different reasons (I am speculating). While mirtazapine is an SSRI ( I think this has been pretty well established), pregabalin upregulates glutamate, not serotonin, which in some pts can have a more profound anti-depressant effect. And unlike trazodone, there have been no reports (of which I am aware) suggesting negative cognitive effects of pregabalin (at modest doses). Is it as strong and effective as BZDs -- no. But is it safer in terms of dependency, I think so. I know that some physicians use pregabalin to help their patients withdraw from BZDs, and that the withdrawal effects of pregabalin are relatively mild in comparison to BZDs (which, as I'm sure you know, are second only to nicotine in terms of the difficulty of ending long-term dependency). Pregaballin, as far as I know (no RCT evidence), is rapidly becoming a first-line anti-anxiety anti-insomnia medication, with BZDs as the second-line. Why? Because if it does work (and it does in a meaningful percentage of patients) then you get most of the benefits with few of the downsides. Of course, BZDs are still therapeutically necessary in many cases, but pregabalin is much less dependence-causing, and much less prone to misuse, than BZDs. And unlike gabapentin, trazodone, and mirtazapine, it has immediate effect that many patients seem to respond to.
With regard to cost, pregabalin is still expensive in the US (and some other countries) where branded as Lyrica. This is partially because Pfizer received a 5-year extension of its exclusivity from the FDA, ending in 2019. In Canada, pregabalin became a generic last year, and its price has fallen dramatically as a result. Perhaps now that Pfizer has a 5-year extension, it will use some of the proceeds to fund some RCTs on the many off-label uses of the medication.
NB) I would be very cautious with quetiapine given the documented possibility of irreversible extrapyramidal side effects in some patients. I don't know many clinicians who prescribe it except when absolutely necessary (say, for BD pts).
Tx Lewis for opening of this interesting question and Devin for interesting answers.
However after this brief discussion I have several comments:
- Lyrica acts primarily on glutamate release (block Ca channels and consequently the release of neurotransmitters is decreased). There is total decrease in noradrenaline, glutamate, substance P etc ...
In addition, there is no action on GABA (direct) and consequently with Lyrica we avoid fast down regulation, which is connected with GABA binding sites!
Why Lyrica acts well for insomnia is not known exactly, however this mechanism is different from those seen in BZDs.
- Lyrica has very strong advantage in compare with other medicals, because its pharmacokinetics (no CYP impact, renal elimination, no DDI almost at all, easy administration etc ... ). These advantages are very important especially when we build huge pharmacotherapy (e.g. elderly patients, patients with multiple diagnoses). As clinical pharmacist specialist i usually suggest Lyrica to the patients with multiple diseases and usually reducing the number of medicals is possible (e.g. antiepileptics as add on indication (levetiracetam, topiramate etc ...) can be discontinued).
- Lyrica is a perfect choice in patients with multiple symptoms and multiple diseases (MDD, pain; anxiety, pain; anxiety, seizures, MDD).
Neuropathic PAIN! The European Federation of Neurological Societies recommends pregabalin as a first line agent for the treatment of pain associated with diabetic neuropathy, post-herpetic neuralgia, and central neuropathic pain.
We know that more than 1/3 of patients with MDD have symptoms of pain and also more than 1/4 patients with anxiety have symptoms of pain. More or less there is a neuropathic pain. In these cases the treatment with LYRICA is highly advisable!
For example: Patients with escitalopram + levetiracetam + valproic acid + mirtazapine + duloxetine (pain) + BZD (insomnia): We can reduce these pharmacotherapy with adding Lyrica and removing duloxetine, BZD and levetiracetam. We reduced the total number of medical per patients for 2 drugs!
- DDI(s) are especially problematic in elderly patients, who are usually treated with several medications and DDI(s) are very complicated, for example: We cannot add duloxetine to the patients with use of ciprofloxacin, which is usually used for urinary trackt infections (upper and lower). In these patients the use of Lyrica is very smart and highly advisable, because we can avoid all DDIs and potential adverse events (blood pressure, rhythm etc.. ).
- problematic patients with cardiovascular events in the past.
Very important in the treatening of psychiatric patients. Usually we have problems with CHF and hypotension, which is occured under psychiatric treatment for insomnia (e.g. quetiapine). and we cannot remove the betablockers, because we minimize the patients' life duration, however hypotension can be life-threatening. If we use Lyrica we avoid all of these problem in the future .... It is true that desensitization of the adrenergic receptors occur, however usually this step is very long (alpha1 and quetiapine).
- how to avoid long term use of BZDs? It is one of the key question when we treated mental disorders. One of the choice can be Lyrica, another one antidepressants, however the use of antipsychotic is not well documented, although the use for this purposes is very big, especially in Europe. I think on long term use it is not appropriate.
Insomnia:
1) sedative antidepressants (trazodone, mirtazapine in non-obese patients)
2) adding Lyrica
3) BZDs only short term use, for example 2-4 weeks (waiting time for maximal effect of antidepressansts)
4) antipsychotics if we do not have another options (e.g. quetiapine).
Often the psychiatrists and GPs do not wait enough time to reach the maximal effect of antidepressants and antipsychotics (wait only one week) and within this time another agent (e.g. antipsychotic) is added and later not removed from pharmacotherapy. Because of these several mistakes patients are overtreated with polypharmacy (psychiatric one). We know that in first week of the treatment there is only 30-50 % reducing in PANNS score or even less in HAMILTOM score and usually I ask myself why patients are overtreated. We know that sedation is common symptom of depression and anxiety disorder and consequently sometimes we should wait and wait instead of inappropriate prescribing, which can have serious impact on our patients.
Best regards,
Matej
Physicians often can't wait because time is of the essence. Also, as Lewis has noted in the past, you can accelerate the time-to-efficacy of ssri/snri by adding buspirone. Are you sure that pregabalin reduces glutamate? If so, how do you account for its anti-depressant properties? Can you cite a paper discussing the pharmacokinetics of pregabalin and in particular its effects on key neurotransmitters? I will look for the paper I read that (I think) showed an upregulation of glutamate, which I may be wrong about. I agree that pts are often over medicated but often clinicians have no other choice without putting the patient at risk of morbidity/mortality.
Dear Devin,
I agree with you about waiting time, usually is also connected with the payers. Before the patients is discharged better economical outcomes we have (less costs for the hospital). It is also one of the main reason for fast swithing and non-waiting. However in primary settings there are more chances to wait. This topic is especially important in the elderly psychiatric patients, where we should wait even more (e.g. 8-12 weeks). If You look STAR-D trial You can conclude that many prescribers do not wait until appropriate time (we do not know the reasons), however it is one of the main reason for treatment failure and polypharmacy. If polypharmacy is used, the discontinuation should be calculated (e.g. quetiapine for insomnia etc ...). This step is smth. missing, especially in elderly patients with dementia.
About buspirone I agree with this suggestion (5-HT1A action). Another option is use of pindolol (a beta-blocker), which can be used especially within the first 2-4 weeks of anxiety or/and depression (nonselective beta blocker with partial beta-adrenergic receptor agonist activity; 5-HT1A receptor weak partial agonist / antagonist (Ki=33nM).
About pregabalin Please see the next paper:
http://www.ncbi.nlm.nih.gov/pubmed/25149863
Pregabalin is not appropriate strategy in 'mono' depression, although it has some positive effects, especially in the patients with anxiety (usually SSRI, SNRI are used before). About up/down regulation ... It is a process, which takes place in CNS. When patient is treated for a long time, usually down regulation takes place (mRNA synthesis-lower produce of new receptors-proteins-less receptors-less action or. activity if a correlation between the binding sites occupationa and effect is well established). In case of so called 'up-regulation' the number of receptors is often higher. This is very important for daily treatment, because we want up-regulation, however it is seen no so often. Up-regulation can be initiated also by another drugs, which can have serious impact on translation (mRNA producing).
Tx Devin for nice discussion!
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