New Painkiller Studies: Working Toward Non-Addictive Painkillers

A decades-long effort among American healthcare providers to better manage pain for a wider range of patients has led to the overprescribing of addictive opioid painkillers, which has led to a nationwide opioid addiction crisis. It is estimated that 2 million to 3 million Americans now struggle with an opioid or opiate addiction and, with opioid-related overdose deaths at an all-time high, research scientists are busy developing non-addictive painkillers that will allow clinicians to prescribe healthy alternative pain therapies for patients who struggle with chronic pain.

Challenges to Prescribing Opioid Alternatives

Experts believe that if the dose is high enough, a person can become dependent or addicted to opioid painkillers in seven days or less. Given the high potential for addiction within a short timeframe, many doctors aim to transition patients to non-opioid painkillers after seven to 14 days. The dilemma is that most non-addictive pain prescription options on the market are more expensive than opioids and aren’t always covered by Medicare and private insurance plans. This makes it challenging for doctors to provide effective long-term treatment for patients who suffer from chronic pain, especially if over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs, i.e., ibuprofen, etc.) don’t provide sufficient pain relief. Therefore, research scientists are also working toward developing non-addictive painkillers (analgesics) that are more affordable.

Non-Addictive Painkillers in the Development Pipeline

A pre-clinical study in mice is underway at Indiana University to explore a new avenue for developing non-addictive painkillers. The Indiana team is one of several medical research teams investigating the use of compounds called positive allosteric modulators (PAMs), which seem to enhance the effect of pain-relief chemicals naturally produced by the body in response to stress or injury. PAMs can potentially provide pain relief without producing physical tolerance (decreased effectiveness) over time, which contributes to dependence and addiction in people who use opioid painkillers. The study of PAMs is a step forward in the search for non-addictive painkillers because these modulators work by targeting secondary drug receptor sites in the body and brain, rather than targeting primary (opioid) receptor sites where drug effects can also influence other systems—like the brain’s reward center—which is where opioids can trigger addiction. Unlike opioids, which trigger an on/off response in the receptor sites, PAMs act as amplifiers that enhance only the brain’s natural painkillers. In this way, PAMs are more selective than opioids or opiates, altering only the biological processes inherent in the body to suppress pain. PAMs specifically amplify anandamide and 2-arachidonoylglycerol, two brain receptor compounds called endocannabinoids, without producing the psychoactive effects or “high” that cannabis does. Other researchers looking into non-addictive painkillers are trying to figure out how to target the opioid receptor sites in the body and brain, but without causing addiction. A University of Michigan study has been testing a compound (a derivative of the opioid orvinol) that simultaneously targets both opioid receptors and nociceptin receptors to give an analgesic effect without the addictive side effects that opioids produce. The orvinol derivative is still being tested in non-human studies. A similar study from Freie Universität Berlin in Germany has been investigating how to refine or alter other opioids so that they relieve pain without causing physical dependence or addiction. The research team in Germany designed an opioid receptor agonist derived from fentanyl that, unlike the dangerous opioid itself, activates the receptors only in inflamed, acidified tissues without affecting receptors in other parts of the body. Using rat models for their study of drugs that relieve inflammatory pain without causing addiction, the team found their new fentanyl derivative to be a strong pain reliever without the side effects of standard opioids. More experiments in human cells are needed to see if this derivative can be developed into a viable non-addictive painkiller alternative. While early study results in the development of non-addictive painkillers are promising, human clinical trials are still some way off; it is necessary to consider other non-addictive painkillers already on the market.

Non-Addictive Painkillers on the Market

In addition to aspirin, there are a few non-addictive painkillers on the market that can provide pain relief, especially when used with complementary modalities like physical therapy, acupuncture, massage and other therapies or lifestyle changes. Some prescriptions for non-addictive pain medications incur an out-of-pocket expense for the patient, or require special authorization from the prescribing physician to get coverage under a healthcare plan. Many people seeking long-term pain relief that won’t put them at risk for addiction find that working closely with their care provider and insurance company to get alternative medications covered is worth the extra effort. Alternative, non-addictive painkillers on the market include:

Celecoxib (Celebrex)

A prescription nonsteroidal anti-inflammatory drug (NSAID) that is taken orally and used to treat most types of arthritis, as well as ankylosing spondylitis and severe menstrual pain, celecoxib reduces the hormones that cause inflammation, pain and stiffness. While very effective as a pain medication, celecoxib or Celebrex is not the right choice for patients at risk for heart disease because it can increase the risk for heart attack or stroke in all patients, especially if taken long-term. Further, Celebrex may cause severe stomach or intestinal bleeding that can occur without warning. For these reasons, close consultation with the prescribing physician at the outset and throughout treatment is required, typically with frequent medical testing to monitor side effects.

Ibuprofen (Midol, Advil)

An oral nonsteroidal anti-inflammatory drug (NSAID) that is available over the counter, but sometimes requires a prescription for higher doses, ibuprofen is similar to celecoxib in that it reduces the hormones that cause inflammation, pain, stiffness and fever in the body. Ibuprofen is used to treat pain associated with headache, toothache, back pain, arthritis, menstrual cramps and minor injuries. Most patients can take up to 2,400 mg per day for pain with relative safety because ibuprofen is not metabolized through the liver as acetaminophen (Paracetamol, Tylenol) is. However, taking NSAIDs such as ibuprofen may increase the risk of heart attack and stroke, particularly if taken at higher doses and/or long-term. Further, because taking ibuprofen and other NSAIDs on an empty stomach can cause irritation or bleeding in the stomach lining, the pills or capsules must be taken with a full glass of water, and ideally with milk or food as well. These risks increase if a person takes NSAIDs with alcohol. Patients with chronic pain may need a higher daily dose of ibuprofen, as well as other therapies for a holistic approach to pain management.

Naproxen (Aleve, Naprosyn)

Another NSAID, naproxen can be taken by patients with arthritis, ankylosing spondylitis, bursitis and gout to manage pain, inflammation and stiffness. These conditions often respond well to a delayed-release oral version of Naproxen (EC-Naprosyn®) at a dose of 375 to 500 milligrams per day. In some cases, the treating physician may increase the dose to 1,500 mg per day. Naproxen’s beneficial effects last a bit longer than those of ibuprofen, so some patients prefer it to ibuprofen for relieving chronic pain. Naproxen carries the same risks for heart attack, stroke and stomach/intestinal bleeding as other NSAIDs and, for these reasons, should be taken with caution. Negative symptoms to look out for include chest pain, weakness, and shortness of breath, slurred speech, stomach upset, and problems with vision or balance.

Diclofenac (Voltaren, Cambia, Cataflam)

The oral version of this NSAID is used to treat mild to moderate pain from osteoarthritis, rheumatoid arthritis, migraine headaches and menstrual cramps. Diclofenac carries the same risks as the other NSAIDs and may require close monitoring and testing throughout treatment, though unlike the others, diclofenac may need to be taken on an empty stomach for greatest effect. It should also be noted that changing brands may require a change in dosage as well, as each brand of diclofenac varies in strength.

Nabumetone (Reline)

Prescribed as an oral medication primarily for pain and inflammation associated with arthritis, this NSAID is effective but has a long list of negative side effects and drug interactions. In addition to the potential for heart attack, stroke or stomach/intestinal bleeding that is seen with other NSAIDs, nabumetone also carries a risk for infertility, among other side effects, and requires close supervision and testing by the treating physician.

Tolmetin (Tolectin – recalled brand)

This oral NSAID can be prescribed as a generic to relieve pain, inflammation and stiffness caused by gout, arthritis, ankylosing spondylitis, sprains and injuries, back pain and sciatica. This medication can be taken on an empty stomach, but may be taken with an antacid to reduce stomach upset. Like nabumetone, tolmetin is an effective painkiller but has a long list of negative side effects and dangerous drug interactions, so close consultation with the prescribing physician is necessary before and during treatment. Before beginning any pain medication, be sure to advise all your care providers if you take aspirin or other NSAIDs and cold medications, as these can have dangerous interactions and increase your risk for very serious side effects. Avoid alcohol when taking any pain medication for the same reasons. Remember, a holistic approach to pain management is considered optimal, where non-addictive pain medication is used in concert with one or more complementary therapies.   Sources: Celebrex (celecoxib)., September 2015. Naproxen., September 2015. Ibuprofen., March 2017. Diclofenac., April 2017. Nabumetone., November 2017. Tolmetin., November 2017. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. Opioids. National Institute on Drug Abuse (NIDA), 2017. “Key Substance Use and Mental Health Indicators in the United States”, Results from the 2016 National Survey on Drug Use and Health. SAMHSA, 2016.

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