Monday, May 27, 2019

What is Pain, and How Should We Manage It?

Today's post is written by a very special friend of mine, Dr. Fred Goldstein. Dr. Goldstein is a Professor of Clinical Pharmacology at Philadelphia College of Osteopathic Medicine. Dr. Goldstein and I go WAY back to when his daughter and I played in the same basketball league as kids.

The topic of today's post is pain, which Dr. Goldstein is a true authority on. He's been teaching about and researching pain for even longer than I've been alive! I learned a ton from reading his article, and I think you will, too. -Travis

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Frederick J. Goldstein, PhD, FCP
Professor of Clinical Pharmacology
Philadelphia College of Osteopathic Medicine

What is pain? Toothache? Sprained wrist? Broken femur? Myocardial infarct (MI)? Obviously, all such conditions are “nociceptive,” meaning they send signals from pathological sites to brain areas for interpretation. Simultaneously activated are emotions which can certainly increase the intensity of such cellular indicators of tissue damage.

However, it is also known that circumstances exist where pain is attenuated or, in some cases, not even felt. A person who has experienced three MIs over the years will probably feel less alarm with a fourth one than the first. Soldiers in a fierce battle may not even be aware of severe wounds until that firefight has ended.

Of course, there is also psychological pain which occurs upon losing a loved one or receiving news that the cancer which has been discovered is, unfortunately, terminal.

Thus, there is always an interplay between physical and psychological aspects of pain.


What about drug addiction? Physical? Psychological? It is now recognized that the clinical problem classified as 'addiction' is a mental disorder, i.e., addiction is psychological dependence.

A person may be addicted to anything if it meets a need, e.g., gambling, shopping, internet surfing, dieting (bulimia), and yes, even drugs. Several major criteria characterize addiction:

1.    Compulsive disorder 
2.    Substantial amount of the addict's time (day and night) devoted to:
a.    Thinking about doing/using it
b.    Doing/using it
c.    Obtaining the necessary money (by legal and/or illegal methods) to continue doing/using it
3.    High rate of recidivism (relapse)

To reduce the stigma of such a term, the preferred designation health professionals are now using is “substance use disorder” (SUD).

There are some data indicating a genetic predisposition to addiction, but the major cause of SUD is truly psychosocial -- and this starts within the family unit. Children will be ‘drug-proofed’ if they receive care from their parents that includes unconditional love, respect and discipline. (I do not mean physical punishment; children should not receive this.)

Also, it is NOT the drug that makes a person develop a SUD. For example, about 10% of those who drink alcohol develop an alcohol SUD. If alcohol were the cause, then everyone who imbibes would develop this. Clearly, we know this does not occur.


For many types of drugs, prolonged use will trigger development of an adaptive process. Tolerance develops. For example, coffee increases stimulation of the brain. Over time, the brain starts to resist the coffee’s effects and becomes normal even though caffeine is in the system. Then the person drinks even more cups every day to achieve stimulation of the brain. The person is now physically dependent.

Over weeks of daily use, patients can also become tolerance to drugs that depress the brain such as benzodiazepines (e.g.,diazepam [Valium]) and opioids (e.g.,morphine).

The major point here is that addiction is NOT the same as physical dependence.


These are effects that occur when a person -- who has been using large amounts of a drug every day for months -- stops abruptly and completely. 

The most common reactions are opposite to the pharmacology of the drug, e.g.,a CNS depressant like alcohol will cause an alcoholic to experience stimulatory effects such as hand tremors and insomnia as the alcohol is eliminated.

In the case of a stimulant drug, coffee is a good example. When a person who drinks many cups of coffee every day stops suddenly and totally, there is now no caffeine in to stimulate the system. The person will feel very tired and may also have a headache. If they continue to avoid caffeine over the next few days, the brain will return to normal. However, if the person resumes drinking many cups of coffee daily immediately, the tiredness and headache will most likely disappear quickly.

Patients who take certain drugs, e.g, opioids, benzodiazepines, daily for more than a few weeks could experience withdrawal reactions if they stop completely and abruptly.

Avoidance of withdrawal reactions is, in fact, the main reason that those with SUD remain connected to their drug of choice. They now are not receiving any psychological effects but continue such abuse to avoid -- or at least reduce -- their withdrawal reactions.

The longer a person takes such drugs and the higher the dose, the more serious the withdrawal reactions will be. In a severe case, a person should be hospitalized where a general approach is to decrease the person’s daily dose by about 10% per day. However, this is very variable, and the ultimate treatment decisions are absolutely based on how the person is doing while going through withdrawal.


Pain is a very important biological signal. In many cases, it is a message that a body part is injured, and one of the best aspects of treatment is to rest that part from which the signal is occurring, at least temporarily. When a person with such pain takes a pain-relieving drug like aspirin (and related medicines like ibuprofen) and then continues to use that part, they will not feel the pain but the injury could become worse.

However, some types of pain are not helpful signals, for example that which occurs in cancer. Often, it can be excruciating. If unrelieved, it can lead a patient to consider -- and sometimes accomplish -- suicide. Any condition that causes this is a ‘Suicidogen’, a word that I coined in 1997 [1]. If you Google this exact word, my paper will come up, usually at the top. In my decades of treating patients to improve analgesia, I know that poor pain management is a suicidogen.

There are several classes of drugs for pain management -- each with some different uses, benefits, and adverse reactions -- which I’ll describe briefly below.

Nonsteroidal Anti-Inflammatory Agents (NSAIDs)

Included in this group are aspirin (ASA), ibuprofen (Advil; Motrin) and naproxen (Aleve; Naprosyn). These drugs work by blocking production of prostaglandins, substances that cause pain and inflammation. They can reduce a body temperature that is elevated above normal (antipyretic action). ASA is also taken daily in a low dose (81 mg) to produce a moderate anticoagulant effect in patients where an intravascular blood clot could cause a serious condition.

NSAID uses include musculoskeletal injuries and pain from bone cancer. Since this latter severe condition is associated with increased prostaglandin production, NSAIDs can be more beneficial than opioids. They are very effective when used properly but daily doses too high can produce adverse reactions, the most common being gastric upset, especially with ASA.

Acetaminophen (APAP)

This drug shares a similar mechanism of action with NSAIDs -- reduction of prostaglandin synthesis -- and some pharmacologic actions, i.e., analgesic and fever reduction. However, it has no anti-inflammatory or anti-platelet action so its effect on prostaglandin is not as powerful as that of NSAIDs. Published data suggest that pain relief provided by APAP is also due in part to activation of descending serotonergic pathways in the CNS [2]. This drug is also combined with opioids in many products designed to treat moderate to severe pain (e.g.,Percocet, which is oxycodone + APAP).

APAP is a very safe drug with good features compared to ASA; e.g., it does not cause gastric upset. However, there is a daily limit recommended by the FDA: 3000 mg. The result of such abuse is serious: possible hepatic (liver) damage sufficiently severe as to require a liver transplant.

Opioids (Narcotics)

Drugs in this classification include codeine, morphine, methadone, oxycodone, hydrocodone, hydromorphone (Dilaudid) and fentanyl (available in a transdermal patch, Duragesic). Hydrocodone is in a combination product with APAP (e.g.,Vicodin).

As is known, endorphins are physiologic substances that decrease pain perception within the CNS by (a) blocking transmission of such signals upward to the brain and (b) decreasing release of pain neurotransmitters in the spinal cord. Opioids act on central endorphin receptors to produce the same effect.

This group of drugs is the most effective for treatment of severe pain, e.g., post-op and in cancer patients. The current opioid overdose epidemic is fueled more by those with an Opioid Use Disorder (OUD) rather than health professionals. Some with OUD steal opioids from their very sick relatives for whom they have been properly prescribed.

The main target is to decrease use in those with chronic non-cancer pain. Patients who have cancer, are under hospice care, or are terminal are exempt from such targeting. However, the FDA has recently issued statements indicating that some prescribers are inappropriately terminating opioids in truly needy chronic non-cancer pain patients. Other meds should be tried separately or added to opioid therapy.

When opioids are taken appropriately under the care of a healthcare professional, adverse reactions are minimal. Initially, patients may become nauseous and sedated but after several days of daily therapy, tolerance develops to them.

However, tolerance does not develop to constipation, so some patients need to be taking stool softeners and other such meds to facilitate defecation. In addition, long-term use can result in decreased production of sex hormones.

There are long-acting opioid products that are very useful for chronic pain management; the fewer times a patient has to remember to take a drug on a daily basis, the higher the compliance rate with using the drug as prescribed. OxyContin (sustained-release oxycodone) is such a product and is a very helpful for managing chronic pain; however, as is clearly known, it has become a product of extensive abuse.


There are many pharmacologic options for treatment of pain that do not involve opioids; they can be alone or concurrently. Decades ago, I added an antidepressant, amitriptyline, to patients undergoing ether cholescystectomy (gallbladder removal) (3) or C-section (4). The doses I employed were lower than those used to treat depression. In both studies, those who received amitriptyline used less opioids after surgery that those who did not receive this antidepressant.

In a pilot study at Philadelphia College of Osteopathic Medicine, I am treating chronic neuropathic (nerve) pain patients with delta-9-tetrahydrocannabinol (THC); this is a product approved by the FDA for reducing chemotherapy-induced nausea and vomiting, and also to stimulate appetite in patients experiencing extreme weight and muscle loss due to severe chronic illness. Several of the patients in my study have experienced significant reduction of their long-lasting nerve pain.

In addition to NSAIDs and APAP, here are various drugs that have been shown to have analgesic actions, either alone or in combination with opioids:

·     Antidepressants 
o  e.g., amitriptyline

·     Anticonvulsants
o  e.g., carbamazepine (Tegretol)
§ gabapentin (Neurontin)
§ pregabalin (Lyrica)

·     Bone-resorption inhibitors / biphosphonates
o  e.g., Alendronate (Fosamax®)

·     Calcium Channel Blockers
o  e.g., nifedipine (Adalat®; Procardia®) 

·     NMDA Receptor Antagonists
o  e.g., detromethorphan; memantine (Namenda)


Pain is an important neurophysiologic process signaling, in many cases, that a body part is abnormal and should be rested temporarily. Taking medications to reduce such pain does not remove the pathological changes; in fact, a major consequence of doing this can be prolongation of recovery. Even more significant, using that part in any athletic event when on such drugs can result in even more severe tissue damage. Using analgesic and related drugs to reduce post-op, cancer, and other medical types of pain is appropriate. It must be understood that it is not the molecular structure of these drugs that cause addiction. 


Dr. Goldstein is Professor of Clinical Pharmacology in the Department of Bio-Medical Sciences at Philadelphia College of Osteopathic Medicine (PCOM) and serves as Coordinator of Pharmacology. His research interests focus on adding non-opioid drugs to improve analgesia in patients who have chronic pain. In addition to his teaching and research at PCOM, he lectures in pharmacology at the University of Pennsylvania School of Dental Medicine. Dr. Goldstein serves on the editorial board of, and reviews submissions for, the Journal of Opioid Management. He is an active member of the National Board of Osteopathic Medical Examiners, where he writes and reviews questions for the COMLEX Level 1 test.


1.    Goldstein, FJ. Editorial: "Inadequate Pain Management: A Suicidogen (Dr. Jack Kevorkian: Friend or Foe?)"J Clinical Pharmacology 37: 1-3, 1997.

2.    Graham GG1, Scott KF. Mechanism of action of paracetamol[acetaminophen] Am J Therapeutics 12: 46-55, 2005.

3.    Goldstein, FJ. "Effect of chronic antidepressant administration upon opioid analgesia." In: Mumenthaler M, van Zwieten PA, Farcot J-M, Treatment of Chronic Pain: Possibilities, Limitations and Long-Term Follow-up·. Philadelphia, PA: Harwood Academic Publishers; (1990): 278-291.

4.    Witkowski, T.A., Leighton, B.L., Goldstein, F.J., Norris, M.C., Arkoosh, V.A. and Bartkowski, R.R., "Effect of Amitriptyline on Spinal Morphine Analgesia" [inelective C-section patients], J Clin Pharmacol 34(10): 1014 (1994).

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