Certain antidepressants can be extremely efficacious for certain pain disorders, most are good for depression, but none of them are “happy pills”. All of the antidepressants affect at least one of three neuro-amines, namely norepinephrine (NE, sometimes referred to as noradrenergic), serotonin (5-HT, 5-hydroxy-tryptamine), and/or dopamine (DA).
The very first antidepressants developed were mono-amine oxidase inhibitors, after discovery that the neuro-amines listed above affected mood favorably. These proved to be very toxic and unfortunately have a significant incidence of food-drug interactions, but they are still used today in refractory depression. The monoamine oxidase inhibors affect all three neuro-amines; NE, 5-HT, and DA. Previous to this, opioids were used for depression because of their euphoric effects until the 1950’s, followed by amphetamines up until the late 1960’s. Today, use of opioids and amphetamines for depression is considered taboo and may be associated with legal issues and potentially malpractice.
HISTORY OF ANTIDEPRESSANTS: The new class of antidepressants in the mid-1900’s were the tricyclic antidepressants (TCAs). These were discovered accidently while pharmaceutical companies were manipulating phenothiazines (chlorpromazine, aka Thorazine® and prochlorperazine, aka Comapzine®) which were used for their psychoactive affects and tranquilizing properties. Imipramine was the first TCA developed followed by several others. Cyclobenzaprine (Flexeril®) was being developed as an antidepressant, but was discovered to be too sedating and ended up being developed as a skeletal muscle relaxant. Cyclobenzaprine is in fact a TCA which was chemically manipulated into amitriptyline (Elavil®). Amitriptyline was shown to have less sedating properties compared to cyclobenzaprine, and better effect on mood. Over the years, several TCAs were developed with more or less serotonin and norepinephrine activity; some had both properties and some had more of one than the other. The mechanism by which all of these work, is to increase the neuro-amine (5-HT or NE, or both) levels within the synapse, by blocking reuptake (sort of like blocking the recycling process within nerves) into the synaptic cleft. The neuro-amines therefore accumulate in higher quantities within the synapse when taking antidepressants. TCAs in general are pretty toxic. They have significant anticholinergic affects similar to sedating antihistamines and atropine. Along with the sedation, this property also causes a drying affect, the result of which is dry eyes, dry mouth, urinary retention, and constipation. Also, the TCAs are anti-arrhythmics carrying a high risk of abnormal cardiac dysrhythmias. Because of all these issues, a safer class of antidepressants with a more desirable side effect profile was sought out.
This led to the development of the specific serotonin reuptake inhibitors (SSRIs), all of which clearly have a better toxicity profile. The first in its class was fluoxetine (Prozac®), followed by many others. Subsequently, we saw the discovery and development of more SSRIs and an additional antidepressant class that added NE activity, and in some cases anticholinergic activity. These included the serotonin norepinephrine reuptake inhibitors (SNRIs, i.e. venlafaxine, aka Effexor®), serotonin antagonist reuptake inhibitors (SARIs, i.e. trazodone, aka Desyrel®), and the atypical antidepressants (i.e. mirtazapine, aka Remeron®). Their activity is summarized HERE.
The bottom line here is that the drugs were intended to treat depression because of an inherent neuro-amine imbalance, which often times is hereditary. If a patient is deficient in 5-HT, NE, or DA, or the balance among them, treatment with these medications, after trial and error, can be quite effective, but is generally even more effective for depression in conjunction with psychotherapy.
PAIN: Several well-controlled clinical studies have proven the usefulness of antidepressants for chronic pain syndromes. A summary of these agents and their respective neuro-amine activity can be viewed HERE. Most of these studies have focused on neuropathic pain because that pain is associated with damaged nerves that are specifically affected by NE. Perhaps the most profound of these studies is Max and colleagues (1992), where they studied amitriptyline (NE & 5-HT) to desipramine (NE only) to fluoxetine (5-HT only) to placebo in the treatment of diabetic neuropathy. Patients receiving amitriptyline or desipramine responded equally well, but those receiving fluoxetine or placebo responded equally poorly. This then tells us that serotonin activity has little usefulness in treating diabetic neuropathy, but norpinephrine in fact is quite useful.
Based on this information, several antidepressant medications were subsequently developed with an FDA approval for pain. The first of these was tramadol (aka, Ultram and not marked as an antidepressant). This one has NE and 5-HT properties plus low level mu-1 receptor opioid agonist activity. The next one was an SNRI, FDA approved as an antidepressant and as a pain medication; duloxetine (Cymbalta®). This was followed by the SNRI milnicipran (Savella®) which is only marked for fibromyalgia as of this post.
The newest of the pain medications having significant NE activity (with significant opioid agonist activity) is tapentadol (Nucynta®). This medication is a Schedule II opioid and is not marketed for depression at all. Online MPA Degrees has an excellent schematic of commonly prescribed medications/pharmacological classes which succinctly clarifies DEA Schedules I through V.
If a patient presents with a neuropathic pain syndrome (i.e. diabetic neuropathy, phantom limb pain, herpes zoster, radicular back pain from spine, etc.) and they are already on an SSRI, a wise option is to consider switching to an antidepressant with NE activity. If sedation is desirable for sleep, mirtazapine or a TCA may be viable options, as both have NE activity and cause sedation. If sedation is not desirable, venlafaxine, (high dose required), duloxetine, or milnicipran would be potential options.
The bottom line here is that all of the antidepressants are potentially useful for depression, but the agents with significant NE activity are most useful for pain management. This is because NE affects pain neurotransmission along the descending central nervous system pathways. Serotonin alone seems to have very little effect when treating pain, unless depression alone is making the pain worse. If a patient is depressed BECAUSE they have pain, simply adding an SSRI will not likely provide much benefit because the blunted mood is a reactive depression from the pain. Therefore, treating the pain is more sensible. ANTIDEPRESSANTS ARE NOT “HAPPY PILLS”. Antidepressants serve to treat depression in patients with an amine imbalance, not a reactive or situational depression caused by pain.
10 thoughts on “Antidepressants are not “Happy Pills””
I have been on Cymbalta for at least 5 years and have tried to quit it once and it was horrible.
I am wondering if Kratom or THC can aid in quitting Cymbalta?
Neither will help. Your doctor could convert you to fluoxetine and then taper that slowly. It’s an easier taper because fluoxetine has a very long half-life.
Dr. Fudin, do you have any knowledge on any interactions or issues between Buproprion and Morphine Sulfate? I take both and the Morphine does not work nearly as well as it used to in the past, and I’m wondering if the Buproprion could be the issue, or if the pain is worse, the brand is different, etc.
All I’ve seen is it may be useful to help block tolerance.
There are no significant drug interactions between bupropion and morphine.
I would love to read an article that discussed all the available treatments for neuropathic pain. I was involved in an accident that left me with neuropathic pain. I had two surgeries and they helped partially, but definitely not enough. I needed those surgeries, but they left me with scar tissue that is frequently very bothersome. My muscle relaxer seems to help with the scar tissue. I take a muscle relaxer (Soma), an antidepressant ( amitriptyline) , and an opiate (Opana ER) to control my pain. The combination works, but not as well as I would like it to. I’m thinking about switching to Nucynta ER or levorphanol. Even though only Roxane pharmaceuticals is the only company still manufacturing levorphanol. I know methadone is suppose to be good for neuropathic pain as well , but my doctor is not a fan of it considering the relatively high accidental overdose rate. Also, methadone has a long and variable half-life. Adding Opana ER to my medicine list was sort of a last resort. I tried all non-medicine methods first like physical therapy and biofeedback. They failed miserably. Then I tried the antidepressants and amitriptyline worked the best. Then I tried anticonvulsants. Then I tried a few opiates. The best medicines in terms of pain relief for me were the anticonvulsants. Lyrica made me 100% pain free. I couldn’t believe it. Unfortunately, I could not continue to take it because of the severe side effects from it. I had severe side effects from every anticonvulsant I tried. And I tried just about all of them. So, as a patient, I do agree that only using opioids is not a good idea when other medicines may be even more effective. If my body was able to tolerate Lyrica, I would throw away all of my other medicines and take only the Lyrica. That is not the case, but I do think patients with nerve pain should try more than just opiates. I do believe opiates should be used as a last resort, except in extreme pain cases.
See Zorn KE, Fudin J. Treatment of Neuropathic Pain: the Role of Unique Opioid Agents. Practical Pain Management. 2011 May; 11 (4): 26-33.
Greg, I’m so glad you commented. You make several valid points! It makes me think that I need to post a blog specific to the treatment of neuropathic pain to include several different therapeutic classes.
Great article. Thank you, Dr. Fudin, for explaining antidepressants so nicely. I have been taking antidepressants for depression, since the days of the Tricyclics. I have since been through trials of many other antidepressants, and these medications have been an essential part of my well-being for many years. I am thrilled that some of the stigma has been removed from the use of these vital medications, but agree that they are NOT happy pills! People who do not have true clinical depression will not suddenly become “happier” with their use, instead, they will most likely just suffer the side effects! There is still so much misunderstanding about antidepressant use and depression. There are also those that like to blame antidepressants for suicides, murders, crimes, and anything else they can think of….instead of the underlying disorder that created the need for these meds in the first place. Yes, there are risks with ALL meds, but like ALL meds, when prescribed and taken properly, by a knowledgable practitioner, they are generally safe.
I agree, that a blog about neuropathic pain treatment would be welcomed. I have suffered from sever acute and chronic pain for many years. It is well controlled with opioids, magnesium, occasional NSAIDS, topical analgesics, an SRNI, and many other PM tools I use. HOWEVER!!!!… I have just been diagnosed with Shingles. My usual pain remedies are hardly touching the burning, searing, jolting, ICE PICK stabs, that are suddenly MY LIFE. I’m pretty unfamiliar with this (near CONSTANT) nerve pain. What do I do? What helps the most? I hate to add more meds to my regiment, but I have to do something to manage this awful temporary (please, GOD) additional pain. I have pretty limited knowledge about neuropathic pain. Anyone?
You might be interested in Treatment of Neuropathic Pain: the Role of Unique Opioid Agents, which is linked on this website.
This sheds light on a number of important points that I think many practitioners overlook when prescribing. I currently do medication reconcilliation at Albany Memorial Hospital and I find many of the patient’s suffering from neuropathic pain are admitted with solely opioid/APAP therapy. These patients are often unsatisfied with their palliative care and end up pleading with their practitioners for upwards titrations of their respective opiates (which they have likely developed a tolerance for).
I am also glad that you chose to close this entry with a reminder that antidepressants are efficacious in cases of amine imbalance, not situational ruts. Many patients with unfortunate circumstances in the absence of neurochemical imbalance find that anti-depressants are comparible to placebo, depreciating the reputation of these drugs. Initial cognitive behavioral therapy to evaluate if there is genuine need for anti-depressant therapy could help prevent a lot of patients from going down a long, dead end road of medication side effects and experimentation.