In 2017, a report from research and consulting institute Altarum estimated that the economic burden of opioid addiction in the US had reached $1 trillion since 2001. The opioid epidemic is now one of the biggest public health crises plaguing the Western world, stemming from the late 1990s, when slow-release opioid drugs were prescribed for pain treatment with assurances that they wouldn’t be addictive.

Overprescription and misuse quickly followed, and the numbers of addicts began to climb. While some of them are able to live with their condition, others move on from prescription medications to heroin or tragically die from an overdose. Patients who truly need opioid painkillers now find themselves having to convince doctors that they aren’t addicts before they can access pain relief.

As a treatment for chronic pain, opioids aren’t ideal for several reasons: the dosage often needs to be steadily increased as the patient develops higher tolerance or opioid-induced hyperalgesia, in which the patient becomes more sensitive to pain with prolonged use of painkillers; they also induce a foggy mental state, leaving the patient less able to function, even though their pain is dulled; and long-term use can result in hormonal changes and physiological or psychological dependence, as well as full-blown addiction.

For almost two decades, the race has been on to find a way around the use of opioids for long-term pain treatment.

Moving away from opioids

One recent development foregoes drugs entirely and directly targets the nervous system. Neuromodulation delivers electrical impulses to the spinal column, nerves or straight into the brain. It’s been used for tinnitus, movement disorders like Parkinson’s disease, hearing and vision problems, arthritis, Alzheimer’s, and sleep disorders, but chronic pain, including complex regional pain syndrome, is one of its biggest targets. The treatment interrupts the pain signal or convinces the brain to stop sending it temporarily, since chronic pain is often a nerve condition rather than a response to true physical trauma.

The pain score is not adequate: we do have to use it, but should also be looking at physical activity levels, pain medication tracking and emotional functionality.

Neuromodulation isn’t addictive and many devices are intended as permanent implants. Unfortunately, however, it doesn’t work for certain types of pain, like fibromyalgia, which is spread throughout the body rather than localised.

The three biggest manufacturers in the field currently are Boston Scientific, Medtronic and Abbott, which distributes a neuromodulation line-up manufactured by St Jude Medical called BurstDR. While the first FDA approval for a spinal cord stimulator was in 1989, it’s only recently that neuromodulation has moved towards being a serious player in chronic pain treatment.

“We’ve seen explosive research in neuroscience and have learned more in the past five to ten years than in recorded history. We’re starting to understand neurocircuitry better: the way we think, form memories, move, dream and how the nervous system is affected by chronic pain,” says Dr Allen Burton, Abbott’s medical director of neuromodulation.

Abbott has pioneered a new type of device that uses ‘burst’ waveform signals developed by Belgian neuroscientist Dr Dirk DeRidder, who is currently the inaugural professor of neurosurgery at the University of Otago’s Dunedin School of Medicine in New Zealand.

Until recently, most neuromodulation or spinal cord stimulation (SCS) was achieved with tonic waveforms (regular pulses keeping to the same amplitude, frequency and pulse width). Burst signals are more powerful and come in groups of high-frequency pulses at lower amplitude, with a break between bursts in order to imitate the way electrical impulses fire naturally in the brain and nervous system.

In clinical trials run by St Jude Medical and published in January last year, patients reportedly had pain levels 5.2% lower when using burst stimulation compared with tonic signals. “BurstDR has been shown to provide less pain, suffering and therapy maintenance. It allows patients to reduce paraesthesia and feel only the absence of pain, with an increased sense of psychological well-being,” explains Burton.

Before burst stimulation was developed, neuromodulation worked by replacing pain with paraesthesia, a tingling, burning or numb feeling akin to a limb that has fallen ‘asleep’. The newer devices ‘talk’ to the brain, sending the message that the body is no longer in pain, so there’s no need to distract the nervous system with a different sensation.

Patients can try out the Abbott devices for a week or two using a temporary implant with an external battery and a remote control. Even if they opt for the permanent implant, the surgery is still reversible. However, any kind of implantation is invasive and stressful for the patient, who could experience the associated risks of complication and infection; they might also, understandably, be unenthusiastic about the idea of electrical leads running up their spinal cords.

Patients are most likely to be put off the idea of neuromodulation by the cost, which can be in the tens of thousands of dollars – particularly when devices are smart enough to link up via Bluetooth through specially designed apps and platforms. Neuromodulation is still a last-resort therapy for many patients, but Burton says Abbott is “working with physicians and policymakers to move neuromodulation earlier in the patient chronic pain treatment continuum”.

Alternatives to consider

Some manufacturers are also examining alternatives that include less invasive options, particularly those known as peripheral nerve stimulation (PNS), where a small wire is placed close to a nerve just under the skin and connected to an external, wearable stimulator.

SPR Therapeutics in Cleveland, Ohio, received FDA clearance in 2016 for a PNS device for acute and chronic pain after it performed well in smallscale studies, in which amputation patients reported a 72% reduction in post-surgical pain.

PNS is also being used to tackle the opioid epidemic on a different front, by dulling the symptoms of opioid withdrawal – one of the biggest reasons why these drugs are so difficult to quit.

Nausea, cravings, anxiety, agitation, muscle cramps, insomnia and depression can start just hours after the last dose and continue for more than a week. It’s not necessarily life-threatening, but it’s unpleasant enough to result in relapse.

In November 2017, Innovative Health Solutions received the first FDA approval for a nerve stimulator device to treat opioid withdrawal. The NSS-2 BRIDGE sits behind the ear to send electrical pulses to cranial nerves for up to five days, getting a patient through the worst of their symptoms. In clinical study, participants reported a 31% reduction in the severity of their symptoms within half an hour; after five days, 88% of them were able to stop using the drug and transition to medicationassisted withdrawal.

Onwards and upwards

The long-term efficacy of neuromodulation for either chronic pain or opioid addiction is still under investigation. Though it’s accepted as safe by FDA, no studies so far have tested an implanted device for more than two years. This is partly because the effects are difficult to measure quantitatively.

“One challenge is subjectivity,” Burton highlights. “The pain score is not adequate: we do have to use it, but should also be looking at physical activity levels, pain medication tracking and emotional functionality. By blending all these together, you get a much better realworld picture.”

Regardless, development is continuing apace. Other devices in Abbott’s line-up are targeting complex regional pain syndrome (CRPS), a condition that sometimes has no discernible cause. It often develops after a limb has been injured, damaging the peripheral or central nervous system. Even after the original injury has healed, CRPS sufferers have severe, prolonged and sometimes constant pain for six months or more, along with fluctuations in blood flow to the area that result in swelling, changes in temperature and increased sensitivity, so that even a gentle touch is painful. CRPS patients often depend on opioid painkillers and they can be hit hard by restrictions intended to cut down on addiction, such as five-day maximum prescriptions. Abbott claims its dorsal root ganglion (DRG) stimulation device is “the first and only neurostimulation device approved only for CRPS”.

We’re starting to understand neurocircuitry better: the way we think, form memories, move, dream and how the nervous system is affected by chronic pain.

The DRG is a nerve bundle found in the epidural space, next to the dorsal nerve root on the posterior side of spinal vertebrae. Until recently, it was thought to have nothing to do with chronic pain; however, over the past five year, studies have confirmed that DRG does, in fact, play an active role. It contains sensory, rather than motor, nerves, which makes it ideal for electrical stimulation, as it won’t result in unwanted muscle twitching. In addition, it’s also already a clinical target for related pain therapies, like radio-frequency ablation, so it’s easily accessible for neuromodulation.

Abbott’s Proclaim DRG neurostimulator targets overactive neurons in the DRG with electrical pulses to “decrease cell excitability” and relieve pain. Because each ganglion is connected to a specific area of the body, the treatment can either be tightly focused on the painful area or cover a broad region, as in standard tonic spinal cord stimulation (SCS), which is effective for less than half of CRPS patients. In a clinical trial known as the ACCURATE study, sponsored by St Jude Medical and published in Pain in April 2017, SCS was compared with DRG stimulation in 152 patients with chronic pain in their lower extremities. An impressive 82.5% of CRPS patients on DRG stimulation reported at least a 50% decrease in pain after three months, compared with 57.5% of those using SCS.

As the cost of opioids tips further towards outweighing their benefits, the need for non-addictive chronic pain treatment grows more urgent. It’s still early days for neuromodulation, but the evidence so far suggests that directly targeting the nerves and neurons where pain originates could be the most effective approach yet.