New and Emerging Alternatives to Opioids for Pain
Lynn Webster
Lynn Webster
Lynn R. Webster, MD Vice President, Scientific Affairs
Opiod opening image pain

Opioids in one form or another have been a mainstay therapy for moderate-to-severe pain, cultivated in early societies more than 5,000 years ago. In the past two decades, problems have emerged in all countries where opioids have been used extensively for chronic pain.

Only a small percentage of people exposed to opioids go on to develop a serious opioid-use disorder. But because opioids have been so commonly prescribed, the number of people who have developed an opioid problem has created a major concern for policymakers, doctors, patients, and society. The consensus is that there must be a better treatment for pain.

Most reasonable people agree that we need analgesics that are safer and more effective than opioids. Fewer than 10 new drugs have been approved for the treatment of pain in the last 20 years.

Today, there are no cures for the disease of pain. There is only palliation.

Challenges researchers face

Drug development for pain has been difficult, because it is incredibly complex. It is even more difficult than finding cures for cancer.

Cancer can reasonably be compared to pain: both are umbrella terms. There are many types of cancer with different types of cellular breakdowns that lead to destruction and death. You would never treat all cancers in the same way: breast cancer obviously requires a vastly different response than melanoma. Pain, too, has various causes and involves many mechanisms. Thus, one type of treatment will not provide relief from all varieties of pain.

Only recently, researchers have recognized that pain can be a disease as well as a symptom, and there are many different types of pain that require targeted therapies, just as in cancer therapy. The problem is that the development of drug therapies for pain is about 60 years behind the science of oncology.

Looking ahead

However, there is hope. Numerous companies are investing in new chemicals that may bring pain therapy into the 21st century with advances that provide substantial improvement over today’s therapies. The new developments could replace the more problematic opioids as we know them today.

Although this article focuses on non opioid therapies, it would be remiss to not mention some of the advances in opioid therapy that will make the products much different — safer and more effective — than the opioids that are used today.

The new developments could replace the more problematic opioids as we know them today.

The Holy Grail analgesic is a drug that would be effective on all types of pain: somatic, inflammatory, and neuropathic. Ideally, there would be no tolerance, constipation, respiratory depression, or abuse potential. Effectiveness would be related to dose, and there would be no dose limits.

Of course, there is nothing available today that comes close to meeting these criteria. But there are opioids in development that lack rewarding properties at analgesic dosages that can lead to addiction or respiratory depression. Opioid-use disorders and respiratory depression are the two worst outcomes from exposure to an opioid.

11 categories of new pain medications that may replace opioids in the years ahead

Opioid Agonists

CARA 845 is a selective kappa opioid agonist. Although it is considered an opioid, it doesn’t enter the central nervous system, which means it cannot cause respiratory depression or addiction. The company developing this drug still has to prove efficacy, but early studies look promising. The drug may be useful in pain that originates in any tissue outside of the central nervous system such as arthritis or visceral pain. Cara 845 has an additional potential benefit of relieving uremic pruritus.

Nektar 181 is a new chemical entity that works by stimulating the opioid receptor. It is an interesting drug because it does not show any rewarding properties, which suggests it is unlikely to be abused or sought after by people who might abuse an opioid. Its slow entry into the brain and low permeability across the blood-brain barrier were designed to reduce side effects, like euphoria and sedation. The company just recently reported favorable results from their efficacy study in people with chronic low back pain. The drug could be useful for patients with persistent, unrelenting chronic pain.

TRV 130 is an example of an opioid-biased ligand. Biased ligands are a novel approach of receptor activation with unique pharmacology. The term “biased” comes from the selectivity of the pathways that are activated vs. those that are not. Opioids traditionally work by stimulating the surface of a receptor. Activation of the membrane of an opioid receptor leads to a cascade of cellular activity that has several different functional effects. The degree to which various cellular pathways are activated depends on the ligand and the receptor. A selective activation can lead to more or less nausea, pruritus, constipation, or respiratory depression. Opioid-biased ligands in development appear to retain their analgesic potency, but may have far fewer side effects and less potential harm because of the selective pathways of activation (or biased activation).

CYT-1010 is a novel analgesic that appears to be more potent than morphine but without the same risk of respiratory depression and abuse potential. It is an analog of the naturally occurring opioid agonists called endomorphins (EMs). The selective activation of a subtype mu receptor is what makes its pharmacologic properties unique. Although still in early development it appears to be effective on acute, inflammatory and neuropathic pain.


Neridronate is a bisphosphonate not yet available in the United States. Bisphosphonates are a class of drugs that prevent the loss of bone mass. They are used to treat osteoporosis and similar bone loss diseases. However, recently, there have been reports that bisphosphonates also may be useful in the treatment of complex regional pain syndrome (CRPS). CRPS is a devastating neurologic disease that cripples people and is associated with a high suicide rate.

Neridronate has been found to be beneficial for up to a year in a small number of patients with CRPS. In small placebo-controlled studies, bisphosphonates showed statistically significant improvement (in CRPS). But there are no long-term studies with this class of drugs, and there are serious side effects that need to be understood before a person begins treatment with bisphosphonates. Yet, because there are no known treatments for this serious disabling disease, bisphosphonates serve as an entry to a potential treatment for CRPS.

Gene Therapy

VM202 (Human Growth Factor) is a new, innovative DNA-based gene therapy that may offer a potential therapeutic option for regeneration of nerve cells. Although the initial primary goal of the drug was treatment for peripheral arterial disease, it is now being investigated as a treatment for diabetic peripheral neuropathy (DPN). This is one of the first gene therapy trials specifically targeting the most common cause of severe neuropathy. If effective, it could be a major breakthrough in treating a very common and highly prevalent disabling pain disease.

Monoclonal Antibodies

There is experimental and clinical evidence that nerve growth factor (NGF) plays a major role in the generation and maintenance of a wide range of pain states. Therefore, there is considerable focus on the development of anti-NGF drugs. In the past several years, numerous humanized anti-NGF monoclonal antibodies (mAbs) have entered pain clinical trials. These studies have shown that anti-NGF mAbs produce significant pain relief and functional improvement in patients with osteoarthritis of the knee and/or hip, chronic low back pain, diabetic peripheral neuropathy, and possibly post-herpetic neuralgia. This is exciting, but it is not clear whether anti-NGF mAbs will be effective and safe for other types of pain.

A downside to this class of drugs is their potential to cause, or worsen, certain pain disorders. Earlier studies suggested anti-NGFs may be associated with accelerated osteonecrosis of the knee. However, subsequent review of the data did not demonstrate a significant relationship. It appears monoclonal antibodies may be effective in treating a variety of pain conditions, but the safety profile is still being defined and more research is needed.

Sodium Channel Blockers

HTX-011 is the combination of a long-acting local anesthetic bupivacaine and the anti-inflammatory meloxicam. The combination of the two drugs appears to provide local analgesia that could last several days. The discovery could reduce the amount of perioperative opioids and provide for quicker recovery from operations where pain has been a limiting factor. It appears that the formulation would be administered by a syringe at the time of surgery or possibly injected in painful areas during the perioperative period.

TV-45070 is a small molecule inhibitor of the sodium channel Nav1.7 and other sodium channels, including those expressed in the pain-sensing peripheral nervous system. The product is a topical ointment intended to be used over painful joints and for neuropathic pain. An interesting finding with this drug is that patients with the genotype R1150W appear to respond better.

NMDA Antagonist

Chronic pain can be maintained by a state of sensitization within the central nervous system that is mediated in part by the excitatory amino acids, glutamate, and aspartate binding to the N-methyl-D-aspartate (NMDA) receptor. A number of antagonists to the NMDA receptor are antinociceptive in animal models but are associated with significant dose-limiting side effects. The NMDA receptor also has a significant impact on the development of tolerance to opioid analgesics.

Although ketamine has been used as an anesthetic for decades, it is now being formulated to be used in sub-anesthetic doses for acute pain and to reverse central sensitizations from chronic pain. In addition, it is anticipated that it will be used at sub-anesthetic doses for post-op pain and possibly for intense spikes of neuropathic pain.

TRP Receptors

Transient receptor potential channels (TRP channels) control how we experience many types of sensations, including temperature, taste, and pressure. Activating or inhibiting the TRP receptors can increase or decrease the sensitivity to a variety of stimuli. For example, activation of TRPV1 can desensitize the pain produced from post-herpetic neuralgia or from pain generated in the pancreas. Other TRP channel modulators could block the pain of sunburns or insect bites.


Palmitoylethanolamide (PEA) is a ubiquitous, naturally-occurring anti-inflammatory and analgesic fatty acid amide. PEA is formed locally at sites of tissue inflammation as a defense and repair reaction. It modulates mast cell activity (hyperactive in inflammatory conditions) and activated glia cells (non-neuronal brain cells). It may be possible to use PEA formulations to treat certain types of nociceptive pain.

Transdermal Vitamin D

Reports indicate that a large number of people in chronic pain have low levels of Vitamin D. It is not clear if this is a coincidence or whether there is a cause and effect. Regardless, restoring normal levels of Vitamin D is associated with reduction in pain and functional improvement. Therefore, treating patients with Vitamin D may be an option for some people with chronic pain.

AAK1 inhibition

Adaptor-associated protein kinase 1 (AAK1), also known as AP2-associated protein kinase 1, is an enzyme that, in humans, is encoded by the AAK1 gene.

AAK1 is broadly distributed throughout the body. When AAK1 is inhibited, spontaneous action potentials from injured neural tissue are suppressed. It is believed that an AAK1 inhibitor has the potential to prevent the development of normal central nervous system windup and to prevent or mitigate neuropathic pain.

AAK1 inhibitors have not yet been studied in humans, but the preclinical work offers promise for an effective anti-neuropathic therapy.

Calcitonin Gene-Related Peptide (CGRP)

CGRP belongs to a group of peptides that act on the calcitonin-like receptor (CLR). CGRP is primarily released from sensory nerves, and thus, is implicated in several pain pathways. It is mostly expressed in C and A delta sensory neurons that mediate pain sensation. Elevation of CGRP occurs when the trigeminal ganglion is activated during migraines. CGRP antagonists have been shown to alleviate migraines. Anti-CLR monoclonal antibodies have also been of primary interest in recent drug development. CGRP is reported to also be a target for treatment of pruritus associated with arthritis and the skin.

Chronic pain may be the world’s most common medical complaint. One in 10 people suffer from chronic pain globally. It certainly is one of the most prevalent and costly public health problems. It is surprising that, as large of a problem as chronic pain is, more drugs have not been developed to treat it.

Although a number of new drugs are now in development for relieving pain, the magnitude of the problem warrants an even larger commitment to discover more treatment options. Perhaps one day an arsenal of therapies will be available for chronic pain. Let’s hope that day comes soon.