Pain Management — Where we stand

In 1999, Henry McQuay reviewed the most frequently prescribed opioids for pain relief and established that morphine, hydrocodone, oxycodone, fentanyl citrate (injection, lollipop, transdermal), meperidine and buprenorphine were the leading drugs at the time. Morphine remains the top choice among intravenous and oral medicines today. Notwithstanding the foregoing, the illegal production of fentanyl citrate, a synthetic opioid, has become a major issue in recent years. In January 2023 Congressman David Trone addressed this issue and stated that a majority of fentanyl on the market is manufactured in Mexico with chemicals from China before being pressed into pills or mixed with counterfeit Xanax®, Adderall® or oxycodone tablets. In addition, in 2018 sufentanil which is up to ten times more active than fentanyl was approved for use sublingually by FDA. It is currently used in the operating theater as an injectable and on an outpatient basis as a transdermal patch. Much like fentanyl citrate, sufentanil citrate binds to and activates the mu-opioid receptor, thereby producing analgesia, respiratory depression, miosis, reduced gastrointestinal motility, and euphoria. A search of Google (using words like illegal use, illegal, etc.) did not yield any information regarding illicit practices.

More than 70,000 people have died as a result of drug overdose in 2021, most of which is attributable to fentanyl citrate. According to the National Institute on Drug Abuse, opioid deaths have steadily increased since 1999. While still our most powerful analgesics, it remains difficult to prescribe opioids optimally because of politics, prejudice, and our continued ignorance.

Despite the fact that opioids are effective for acute pain, they are not effective for many chronic pain conditions, and as is well known, are associated with significant addiction risks. So, what do we do? Over-legislation is not the answer. However, training physicians and therapists may offer an alternative to those who must address acute pain, but as well provide support to mitigate the potential for addiction.

Chronic (long term and persistent) lower back pain and headaches are the most commonly diagnosed chronic pain conditions among adults in the United States. The most common prescribed drugs to treat lower back pain are nonsteroidal anti-inflammatories. These include ibuprofen, acetaminophen, naproxen, and cyclobenzapriene. Ibuprofen and acetaminophen have been taken together and may act synergistically. While in the 1990’s, opioids (natural and synthetic) were often prescribed, in particular oxycodone, these pain relievers are potent, potentially addictive, and today are less often prescribed. In a meta-analysis completed in 2021, the most prescribed drug to treat lower back pain was ibuprofen. Tramadol, another synthetic opioid is also used to treat lower back pain.

For general pain management, in addition to the foregoing nonsteroidal anti-inflammatory medications described above, aspirin and aspirin/citric acid/sodium bicarbonate are the most commonly suggested OTC drugs.

In addition, lidocaine patches, TENS (Transcutaneous electrical nerve stimulation) application, and acupuncture, are known to relieve localized pain.

Drugs commonly prescribed for depression have been used for pain relief, particularly for osteoarthritis and neck pain. These include duloxetine and amitriptyline (and other tricyclic medications).

Neuropathic pain may be described pain arising from a lesion or disease of the somatosensory nervous system. The management of neuropathic pain involves treating the symptoms, rarely being able to address the underlying cause. A meta-analysis on drugs used for this condition was conducted with 229 studies thus far. The Special Interest Group on Neuropathic Pain (NeuPSIG) recommends a number of medicines as an initial treatment, such as gabapentinoids, tricyclic antidepressants (TCAs), and selective serotonin–norepinephrine reuptake inhibitors (SNRI). Lidocaine, capsaicin, and tramadol are considered second-line treatments, while morphine and oxycodone come in third as strong opioids alongside botulinum toxin-A (BTX-A) specific for peripheral neuropathic pain.

A word of caution on taking pain relievers. The patient may be masking an underlying problem which could lead to further complications in the future. It is always best to consult your healthcare provider when taking medications. In addition, all of these medications have side effects which in some cases can be life-threatening when used over long periods of time (peptic ulcers, addiction, hallucinations, dizziness, diarrhea, constipation, renal failure, stroke, respiratory effects, myocardial infarction, etc.).

New drug therapies continue to be developed that hopefully will supersede the benefits of opioids without concurrent addiction. While still in the experimental stage, talarozole, formerly an investigational drug for the treatment of acne, psoriasis and other keratinization disorders is now being considered as a potential treatment for osteoarthritis in the hand. Researchers observed that when mouse knee joints were destabilized 6 hours after talarozole treatment, it suppressed inflammatory genes in the cartilage and reduced cartilage degradation and osteophytes after 26 days. Thus, boosting all-trans retinoic acid suppresses the inflammatory response to mechanical injury, in articular cartilage in vitro and in vivo, indicating RAMBAs are potentially disease-modifying drugs.

In May 2019, the FDA granted priority review status to the combination drug. In July 2020, the FDA has approved the combination of orphenadrine citrate, aspirin, and caffeine 50 mg/770 mg/60 mg (Orphangesic Forte, Galt Pharmaceuticals) for mild to moderate pain.

There has been a discovery of a potentially new non-opioid painkiller (analgesic) with potentially fewer side effects compared to other potent painkillers.

It has been found that benzyloxycyclopentyladenosine (hereinafter BnOCPA) is a potent, selective and non-addictive analgesic that works well in test model systems, according to a team at the University of Warwick. Additionally, BnOCPA has a unique mode of action, opening up a new pipeline for the development of new analgesics.

There are many drugs that work by activating adapter molecules called G proteins on the surface of cells. Activating G proteins can lead to a large number of cellular effects. Unlike other G proteins, BnOCPA only activates one type of G protein, so side effects are minimal.

According to Professor Graham Ladds, BnOCPA has the potential to be a new type of painkiller, as well as an effective method for targeting other GPCRs in drug discovery. BnOCPA’s unique mode of action and specificity for a particular type of G protein could potentially lead to the development of a new class of analgesics with fewer side effects compared to traditional opioids.

However, it’s important to note that while the initial results in test model systems are promising, further research is needed to determine the safety and efficacy of BnOCPA in humans. Additionally, drug development can be a lengthy process, and it may be several years before BnOCPA or any related compounds become available for clinical use.

Dr. Khanna and his team have developed a promising new compound, 194, that might be used to regulate NaV1.7 activation and relieve pain. Compared to previous attempts to block NaV1.7 directly, 194 indirectly regulates it and has been shown to reverse pain in animal models across multiple pain models and species, including humans.

There is evidence that 194 may promote pain relief by activating the body’s endogenous opioid system, which can produce pain relief without causing negative side effects such as decreased motor performance, depressive symptoms, or addiction. In addition, the team observed synergistic effects when 194 was combined with morphine and gabapentin, suggesting that it could be used as a dose-reduction strategy for painkillers with negative side effects.

These findings show promise and may represent a significant breakthrough in pain management, offering a new approach that could be more effective and have fewer side effects than current approaches.

Besides TENS, there are newer non-drug techniques that can alleviate pain in many parts of the body. For example, the FDA approved a prescription wearable Nerivio® (developed by Theranica) as a dual-use acute and preventative treatment for migraines. Steven Tepper et al. reported that Nerivio® demonstrated significant reductions in monthly migraine days and other prevention end points in a randomized, placebo-controlled study. The conception for this device is based on Conditioned Pain Modulation (CPM), one of the human neural systems that control pain. CPM is an endogenous descending pain inhibition mechanism located in the brain stem, the most primitive part of the brain that controls nociception (sensory nervous system process for encoding harmful stimuli) and pain. Despite being an endogenous mechanism, CPM is often deficient and not triggered in people with certain neurological disorders.

A smartphone is used to control the Nerivio®, which wraps around the upper arm and activates peripheral nerves through non-painful electrical modulation, causing conditioned pain to be modulated in remote areas. Theranica has increased the number of migraine treatments per unit by 50%, from 12 to 18 treatments per unit. Each treatment lasts 45 minutes and is recommended every other day for prevention or at the beginning of a migraine attack for acute treatment.

A Nerivio app allows users to customize their migraine treatments, receive reminders for preventive treatments, track their migraine patterns and optionally share migraine data with their doctors. A Guided Intervention of Education and Relaxation, which uses techniques such as diaphragmatic breathing, muscle relaxation, and guided imagery, is also included in the app.

Advances continued to be made in the area of pain management. While opioids are still a part of the pain management landscape, as precision medicine becomes more dominant in the area of pain management, it is hopeful that new drugs and methodologies can be discovered to mitigate acute and chronic pain.

Written By: Lawrence D. Jones, Ph.D.

Keywords: pain management, fentanyl, migraine