Tag Archives: antidepressant

NY – Beth Israel Medical Center

Russell Portenoy, MD
Pain Medicine Specialist
Chairman, Department of Pain Medicine and Palliative Care, Beth Israel

Depression and Chronic Pain Is Extremely Common

In some patients, depression follows the pain, and if you can effectively treat the pain, the depression would get better. And in some patients the depression seems to drive the pain, says Dr. Portenoy. He explains that when these two conditions coexist, patients need carefully coordinated treatment.

Dr. Portenoy is among New York Magazine’s “Best Doctors” for 2008, as listed in the June 16, 2008 edition of the magazine. The New York Magazine list is excerpted from Castle Connolly’s annual guidebook, “Top Doctors: New York Metro Area.”


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Questions About Using Opioids for Chronic Pain

Q: Would you say that opioids are a last resort?

A: No. Opioids should be considered for every patient with chronic, moderate to severe pain, but in every case, you would only prescribe the opioid after carefully considering the responses to several questions.

Q: What are those questions?

A: First, what is typical treatment with respect to this pain? Second, is there some other therapy that has as good or better efficacy and safety? Third, is this person at relatively high risk of opioid side effects for whatever reason? And fourth, is this patient likely to be a responsible drug taker, or is there a history of substance use problems?

So in some cases, for example a patient with severe pain who has not done well with several steroid or other drug injections and physical therapy, and who presents to the doctor with back pain so severe that he can’t walk—that patient might be considered a candidate right then for a trial.

Q: What is an example of that review process with a typical patient who has arthritis of the knees and hips.

A: Everybody would agree that the first-line therapies typically would include acetaminophen, physical therapy, or a TENS unit, or maybe—if there’s a single joint that has some swelling—an injection.

The next-line therapy would be an NSAID. But if that person has a history of an ulcer or a history of bad heart disease, the NSAID risk gets to be relatively high. So that patient might be considered for a trial of an opioid at that point.

Q: If I’m that patient and I’m put on a trial, how will I use the drugs?

A: Almost everyone with chronic pain appears to benefit more from regular, fixed, scheduled use as opposed to PRN [when needed] use. There is a general perception, two decades old, that patients do better if they have pain medicine in their blood 24/7. It’s done in a sustained way, so that the blood levels don’t fluctuate much.

Q: In the whole range of treatments for chronic pain, where do opioids fit in?

A: The chronic use of opioid therapy to treat noncancer pain syndromes, such as headache and low-back pain, and arthritis, continues to be controversial. Most pain specialists nowadays would say that opioids might be considered in any patient who has chronic, moderate to severe pain, but generally should only be implemented if there are no other treatment options that have a favorable and safe effect. The shortest way of saying this is that most pain specialists would not consider opioids first-line treatment for chronic noncancer pain except in highly selected patients.

But we have accumulated clinical experience that suggests the following: There is a sub-population of patients with chronic pain, who can be given access to long-term opioid therapy, and they will experience sustained and meaningful control of pain in the absence of intolerable side effects and without the development of tolerance or the need for dose escalation. And they will not develop any aberrant drug-related behaviors consistent with abuse, diversion, or addiction.

Q: What about the use of opioids for breakthrough pain?

A: It looks like about 60% of patients with chronic pain have flairs that can be called breakthrough pain, and in the cancer population, the use of a short-acting opioid co-administered with a long-acting drug is the standard of care.

With noncancer pain, it’s a moving target. People are trying to figure out if it should be the standard of care or not. I think it should not. I think it should be a case-by-case decision.

Q: What are some of the risk factors when opioids are being considered? Do they all relate to addiction?

A: No. Suppose you have a patient with very bad lung disease who might be at risk for the respiratory effects. (Opioids can suppress breathing.) Or you have a patient who has severe gastrointestinal problems—where the constipation induced by the opioid might become very problematic. Or you have an elderly person with arthritis who has a mild dementia: In that case, the bias would be to try an NSAID because the opioid has a higher likelihood of causing cognitive impairment.

Q: Is the ultimate concern, though, addiction?

A: No, it’s broader than that. It’s responsible drug use, a term I use purposely because for clinicians, addiction is an uncommon problem—a very, very serious problem, but it’s an uncommon problem.

Q: So there are irresponsible uses that do not involve addiction?

A: What’s much more common for clinicians than addiction is what has been called aberrant drug-related behavior. Behaviors like doctor shopping or frequent visits to the ED [emergency department], or increasing the dose during pain flare-ups without permission. Or taking an opioid to help you get to sleep at night, or taking it when you’re feeling anxious. Or in some cases using an illicit drug, like smoking marijuana on the weekend, without telling you.

A clinician who is trying to prescribe these drugs safely ought to be monitoring all of those behaviors and trying to work with the patient so that the behavior regarding these drugs is responsible—meaning take the drugs as prescribed.

Q: It’s not as simple as saying that opioids deliver a “high,” is it? What “benefits” do abusers get from the drugs?

A: There are studies that have been done that show that in the usual person—with no history, and no family history of addiction—the typical mood response produced by opioids is dysphoria, not euphoria. But in some cases, they might be driven by co-morbid psychiatric disease—they may have anxiety disorder and realize that these drugs produce some reduction in anxiety. Or they have a depressive disorder—these drugs were used in the 1950s as antidepressants before we had any real antidepressants.

Or the patient may have a co-morbid psychiatric disorder associated with impulsive drug use—they would take any centrally-acting drug, any drug that alters their consciousness, impulsively.

There are also people who have an addiction biology, and it’s profound. I talked to a physician who became addicted to opioids, and he told me that the first time he took an opioid, it was like he had discovered something very magical about life. He said, “I knew this was my substance, this was something that I needed.” With a single dose.

Q: What is the risk of actual addiction?

A: Most scientists who work in this area think that about 10% of the population in developed countries have the biological predisposition, the genetic predisposition, to potentially become addicted. Truly addicted. Which is a huge number, 10%.

Q: If a chronic pain patient passes your various tests and is a good candidate for an opioid, what happens then?

A: At the present time the professional community is telling doctors that they have two obligations whenever they prescribe a controlled prescription drug.
Number 1: To know the pharmacology so that the patient’s outcomes—meaning the pain relief they get, and the side effects they experience—those outcomes are optimal.
Number 2: They need to do risk assessment and management to ensure that the patient takes the drugs in a responsible way, and there is minimal risk of abuse, diversion, and addiction.

Q: What does that mean for the patient’s experience?

A: Every patient should undergo a comprehensive assessment and risk stratification. The doctor takes a history and then makes a decision: Is this person at high risk or at low risk of developing problematic drug-related behaviors?

The most accepted factors that put a person into a high-risk category is a personal history of substance abuse now or in the past, a family history of substance abuse now or in the past, or a history of major psychiatric disorder. And there are many, many other factors: Current smoking, history of physical or sexual abuse.

Q: Give an example of a high-risk patient.

A: A young man who injures his back at work and has pain for six months, sees a doctor, and the history reveals that the patient binge drinks on the weekend, uses marijuana three nights a week, and has a brother who has been through detox. If an opioid is being considered for that patient, then the structure of the therapy should be very defined and very rigid, it might include any or all of the following.
An opioid agreement that is used to educate the patient about responsibilities and consequences of bad behavior
A small number of pills prescribed
The requirement that the patient returns with the pill bottle so that a pill count can be done
The requirement that the patient gets urine drug screens periodically
A requirement that the patient gets a consultation with an addiction-medicine specialist
The requirement that the patient uses only one pharmacy, so that you can track what has been dispensed

Q: What about a low-risk example?

A: A patient 70 years old develops bad knee and hip pain from arthritis, and the history reveals no personal history of substance abuse, including no use of alcohol, no family history, and no known psychiatric disease—that patient has very, very low risk of developing problematic behaviors. For that patient, a structure might be to come back in a month and provide a phone call in the middle.

Q: Sounds complicated. Should chronic pain patients seek out a specialist?

A: Only about 5% of people with chronic pain ever see a specialist. This is a type of therapy that, for 20 years, people like myself had been promoting as needing to be done by primary care doctors.

Q: What advice do you give patients who are looking for possible opioid treatment?

A: I would like patients to think, “Opioids may or may not be appropriate. But I need to see a physician who’s comfortable with prescribing opioids and also knows how to do it in a way that’s safe and effective for me. When I go into that physician, I know that I’m going to have to be honest and let that person do a good assessment. And I’m going to have to provide my records to that person. If that means that I have to have urine drug screens, so be it. If I have to sign an opioid agreement, if it’s reasonable and educational, I’ll sign it. If I have to go and get treated by a psychologist at the same time and I can afford it, I’ll do it.”

There has to be a recognition that this is a controversial therapy that takes a lot of effort on the part of the clinician, and the patient has to not only adhere to the therapy, but also has to communicate and be willing to be monitored.

Q: Given all that, do you believe that opioids are underused in the treatment of chronic pain?

A: Absolutely. I’ve seen this controversy in the U.S. going back and forth for about 25 years. This is a pendulum that swings back and forth depending on how frightened people are of addiction and abuse, and depending on how much the advocacy community gets the word out about undertreatment.

There’s a whole political and social context here that is not based on any known science. And in the 2000s we seem to have the pendulum shifting toward more denial that the therapy can be useful, more reluctance to prescribe, more concern about regulation.

Q: That’s an unfortunate swing for those people who would benefit from these drugs.

A: No question. But I want to acknowledge what my colleagues would say, many of them—that 25 years of research has yet to show the evidence that long-term opioid use is effective for chronic pain.

There have been a large number of good clinical trials, but they’ve all been either short-term or in very selected populations, or didn’t measure all the issues.

But the bottom line is that we have about 9,000 years of clinical experience showing that they can work. And you also have a consensus in the professional community of pain specialists—not just in the U.S., but also in Canada and England and other countries in Europe. You have a consensus that has evolved based on the data that do exist and the observations that exist.

The real issue is, let’s stop arguing about should patients ever get opioids and start arguing about who should get them and how you prescribe in a way to optimize the outcomes.

Q: Of course, even when drugs work, patients don’t always take them.

A: In the past 20 years, there’s been all of these new modified-release formulations, so now there are once-a-day drugs, twice-a-day drugs, patches that last three days, all for the treatment of chronic pain.

So you would think that compliance would be easier because it’s more convenient, and in some respects that’s true. But we just did a little study here, which we haven’t fully analyzed yet or published, and what we discovered in our group was this: In almost 100 patients, about 50% were non-adherent, and the vast majority of that group was undertreating.

It raises questions: Why are they undertreating? Are they afraid? Or do they have side effects? Is it money?

The bottom line is, most patients are not out there acting like [drug addicts], most patients are pushing you to give less, or not taking everything you prescribe. They’re not interested in abuse, they’re interested in getting off this stuff!

Phantom limb pain

Phantom Pain is a form of nerve pain appearing to arise from an area of the body that has been removed or amputated. This pain can affect mastectomy patients as well as patients with simple tooth extractions. Phantom sensations of some kind are almost universal in patients that have undergone limb amputations. Significant pain occurs in as much as 80% of these patients, but seems to improve over time in at least half of these patients.

The cause of phantom pain is not fully understood. It is important to emphasize that the pain is not imagined, and is not the result of a psychological or emotional disturbance.

Phantom pain is the prime example of neuropathic pain; i.e., pain that is caused by a damaged or malfunctioning nervous system. Therefore, all the medications that are used for neuropathic pain can be useful for phantom pain. This includes anti-convulsant and antidepressant medications. Transcutaneous electrical nerve stimulation (TENS) of the stump can occasionally provide relief. Interestingly, stimulation of the intact, opposite limb is often more effective. In some patients, rehabilitation with active exercise and use of the stump and a prosthesis can be the most beneficial treatment. Placement of spinal electrical stimulators has had mixed results, but if the pain has been refractory to all prior treatments then this should be considered.

It may be most appropriate to target the initial injury that precipitates the enduring neuropathic pain. In fact, this is already done by the use of pre-emptive anesthesia during surgery. The surgeon uses a local anesthetic to deaden the nerves as well as a general anesthetic to immobilize the patent for surgery. Another possibility may be to suppress the immune system for the initial five days after injury. This may curtail the inflammation associated with peripheral nerves that appears to trigger many aspects of neuropathic pain.

A recent article in Psychiatric Times by Steven A. King reported that while the “apparent neuropathic nature of phantom limb pain (PLP) would suggest that antidepressants, anticonvulsants and similar medications would be most efficacious. Most (PLP) patients are treated with acetaminophen, nonsteroidal antiinflammatories and opioids.” A survey article by M.A. Hanley and associates found that just over half of PLP patients, and over one-third of severe PLSP patients, “had never been treated” at all for their pain.

from The Richeimer Pain Institute

Antidepressants Linked to Suicide?

The FDA urged drugmakers to put new warning labels on popular antidepressant medications. Alerting to watch for suicidal tendencies, hostility and agitation in patients taking the drugs.

FDA focuses on Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro, Wellbutrin, Effexor, Serzone and Remeron and follows a warning by the British government last year advising physicians not to prescribe most widely used antidepressants to children.

FDA said it does not know whether the medications are responsible for reported side effects such as inner restlessness, agitation and suicidal thoughts in some people. Officials said they are drawing greater attention to known cautionary information while a team of outside researchers completes a comprehensive analysis of the possible risks.

Critics of the medications demanded that the FDA go further. Although Prozac is the only one of this class of drugs that has been specifically approved to treat depression in children, doctors are writing tens of thousands of prescriptions for many of the others, based on their clinical judgment that the drugs are safe and effective.

Many critics complain that a majority of studies of the drugs in children found that the medications did no better than dummy pills in treating depression, but that these studies have been hidden from doctors and the public. The companies say the studies are proprietary.

Many psychiatrists say the medications save lives and warn that discouraging patients from taking them could lead to greater numbers of suicides. They insist that suicidal tendencies or attempts among patients taking the drugs are the result of underlying disorders, not the medications.

The Public Health Advisory containing the new label warnings and cautions is available online at http://www.fda.gov/cder/drug/antidepressants/default.htm



i) Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for 150 years in Europe, and probably for a great deal longer in the East, in the form of willow bark extract. Useful when given appropriately, examination of the chronic pain population indicates that a very high number of patients are intolerant to these drugs because of gastrointestinal or other side-effects. There are two possible hypotheses for this. Firstly, chronic pain sufferers tend to be somewhat hypochondriacal and intolerant of body symptoms in general and thus less tolerant of real or perceived side-effects when taking medication. The second is that there may be a sub-group of patients whose pain is not managed well early on. NSAIDs may produce side-effects, limiting their use. With no pain relief, the patient fails to exercise. This hampering of their rehabilitation because of inadequate analgesia may contribute significantly towards the chronicity.

Recently COX2 antagonists have come on the scene, but the first wave of these have been disappointing in the UK, in that the side-effect profile does not appear to be particularly better than the present drugs (Meloxicam, Etodolac). The newer drugs, Vioxx and Celebrex, are now available in the USA and will soon become available in Europe. Their arrival is awaited with eager anticipation, but the results may prove to be disappointing. The products may not be as side-effect free as they first seem.

ii) The use of opioid drugs for the management of chronic non-malignant pain is fraught with difficulties, some real and some perceived. Morphine itself has tended not to be prescribed for chronic pain, because of a fear or stigma concerning Morphine. Physicians may fear dependence, tolerance and side-effects. There is a wide difference of opinion, which is still to be resolved; however, some patients can have their pain adequately controlled with opioids, without an unacceptable level of addiction problems. The potential risk of addiction remains a very real problem for a minority. Also, a significant number of patients with chronic pain complain of bothersome side-effects from medication. Mobility and distress must be monitored and benefits must accrue in both these parameters, as well as in reduction of pain.

iii) In the UK and in the USA, traditionally most patients with chronic pain receive an opioid derivative such as Codeine, Dihydrocodeine or Dextropropoxyphene. In the past Pentazocine and Buprenorphine enjoyed a passing vogue but are now little used. Pentazocine proved to have unacceptable side-effects, and Buprenorphine, originally thought to be non-addictive, was shown to have addictive potential and since being classified as a controlled drug has enjoyed little popularity. Nefopam has limited efficacy and popularity, and Meptazinol is short-acting, and often associated with an unacceptable level of side-effects.

Recent work suggests that Codeine and Dihydrocodeine are merely pro drugs for Morphine, and exert their action through metabolism to this compound. Given that a significant number of the population do not have the metabolic pathway to facilitate this, it is not surprising that there is a significant failure rate to produce any analgesia at all and that patients getting analgesia seem to get limited relief-hence possibly the popularity of these preparations being compounded with Paracetamol. There is good evidence that in some patients, much of the analgesic effect in these combined preparations lies with the Paracetamol itself, whilst many of the side-effects lie with the opioid.

v) Tramadol hydrochloride is an orally active, clinically effective, centrally-acting analgesic. It can produce analgesia that has been compared to Codeine or Dextropropoxyphene. It has been used in post-surgical pain, obstetric pain, cancer pain and chronic pain of mechanical and neurogenic origin. Analgesic tolerance is not a significant problem, and psychological dependence and euphoric effects are minimal. There are a significant number of patients in the chronic group who develop side-effects, but many of those who tolerate the drug get useful benefit in pain reduction. This slow-release formulation is an appropriate vehicle for chronic pain management.

Tramadol has an affinity, albeit relatively weak, for mu opioid receptors. It is also a neuronal uptake inhibitor. The monoamine neurotransmitters 5HT (Serotonin) and Noradrenaline (NA) are involved in the inhibition of spinal cord dorsal horn neurone responses to painful stimulation (i.e. closing the gate). Analgesia can result from activating the pain inhibitory pathways originating from higher CNS levels, and containing these neurotransmitters. Tramadol inhibits the uptake of 5HT and Noradrenaline but not Adenosine, Cyclic AMP, Dopamine, or Gaba.

Metanalysis by Moore and McQuay indicates an appropriate dose response curve for Tramadol, and suggests a reduced number needed to treat to show therapeutic efficacy as compared with Codeine, in doses of 75 to 150 mg. Nausea, vomiting and dizziness are greater than with Codeine, somnolence about the same and constipation much less. In the chronic pain situation nausea and vomiting are attenuated with usage, as is somnolence for both drugs, but constipation remains a particular problem with Codeine and Dihydrocodeine, and less of a problem with Tramadol.

Side-effects from Tramadol can be minimised by starting with a low dose and increasing gradually. There is evidence that this reduces the side-effects and improves tolerance. According to need, it can be started in a low dose of 50 mg daily or twice a day, and gradually titrated to reach 50 mg three times a day by day 3. Once a patient is established on a therapeutic dose, they can be put on the slow-release formulation to provide round-the-clock analgesia.


i) Anticonvulsants are well acknowledged as being effective in the management of shooting pain, for example: trigeminal neuralgia and the shooting element of neurogenic pain, such as post-herpetic neuralgia, diabetic neuropathy and similar conditions. Carbamazepine appears to be the most effective drug although there is a higher incidence of side-effects than with Sodium Valproate. Recently Gabapentin and Lamotrigine are enjoying popularity, either as “add on” drugs, or as sole agents. Further drug development of these types of agents might produce useful efficacy in the future.

ii) Tricyclic antidepressants are one of the most commonly used analgesics in pain clinics. This is not for the specific antidepressant action, but is more associated with the activation of pain inhibitory pathways. This appears to be less of a feature with the tetracyclic agents, and has meant that their usage in chronic pain has as yet remained unproven. This is of course is disappointing as the side-effect profile is significantly better. The sedative effect of Amitriptyline can be harnessed to good usage by giving the tablet one or two hours before retiring, and it should not be used during the day.


In general, patients with pain can be given a trial of Paracetamol. An appropriate non-steroidal can be used if there is an inflammatory process, and continued if these are effective and if side-effects are minimal. The next optimal step in the analgesic ladder will be the use of agents like Tramadol, Dextropropoxyphene, or Dihydrocodeine, with long-acting preparations being ideal for chronic pain. At present, slow-release Tramadol would appear to be the most effective drug in chronic pain for this group of patients. If side-effects preclude its usage, one of the other agents can be considered.

Finally a small group of patients might be suitable for the use of opioids themselves.

In conjunction with this ladder, anticonvulsants and tricyclic antidepressants can be considered, for their specific and appropriate actions on shooting and burning pain, usually of neurogenic origin.