BBI Contributing Writer

It's arguable that death is not man's enemy, because it is inevitable (like taxes). But pain, that's another story. Some 2,500 years ago, the Greek playwright Aeschylus wrote "Who, apart from the gods, is without pain for his whole lifetime?" It was a rhetorical question maybe one of the first such. And pain is not a uniform experience; the French novelist and poet Victor Hugo commented, "Pain is as diverse as man. One suffers as one can." Its effects can range from trivial to devastating. In the words of the American writer Mason Cooley, "With every physical pain, my moral fiber unravels a little."

Hardly surprising, then, that the relief of pain has been a major preoccupation of mankind since our ancestors stubbed their toes coming out of their caves. There are fat volumes to be written indeed, they probably already have been tracing the history of pain relief in all the major cultures of the world. But the problem of pain is unsolved. It remains a major hindrance in the management of conditions such as chronic arthritis, malignancy and the aftermath of surgery. And since demographic trends are laying more and more people open to the risk of severe and unremitting pain in age-related conditions, pain management is now at the top of the medical agenda.

Traditionally, relief of pain has been achieved (or attempted) by pharmacological means. The modern era of analgesia was ushered in by aspirin, which in addition to all its other more recently uncovered virtues remains a highly valued analgesic for mild pain. The World Health Organization (Geneva, Switzerland) has devised an "analgesic ladder," starting with drugs for mild pain (aspirin, paracetamol, NSAIDS); progressing to dextropropoxyphene, dihydrocodeine and codeine for moderate pain; and for severe pain, opioids including morphine, oxycodone, fentanyl, buprenorphine, dextromoramide, hydromorphone and methadone.

This is an impressive-looking armory and one might easily imagine that one or more of these agents would be equal to any degree of pain. The problem is that they all have drawbacks notably sedation, constipation and habituation in the case of the opioids. In unremitting pain, they have to be given around the clock. And not all potent analgesics are useful in all kinds of pain; they tend to be less effective, for example, against neuropathic and intermittent pain.

New drugs, new deliveries

Advances in the pharmacotherapy of pain have been and are being made on two fronts: new drugs and new delivery technology. A focus for new drug development is the NMDA receptor. N-methyl-D-aspartate (NMDA) receptors in the spinal cord mediate the pain signal transmission, and also trigger some local mechanisms to regulate responses to painful stimulation. Wang and associates from Tianjin University General Hospital (Tianjin, China) examined the effects of a noncompetitive antagonist of NMDA receptors, MK-801, also known as dizocilpine, on NMDA-mediated processes. They found that blocking spinal cord NMDA receptors with MK-801 may attenuate peripheral inflammatory pain and could play a role in pain management. Unfortunately, longer-term treatment with most high-affinity NMDA-receptor antagonists has been associated with serious adverse effects, including memory loss.

One agent that may offer a superior profile is memantine, which belongs to a class of noncompetitive NMDA-receptor antagonists. Because the drug selectively targets pathologic, but not physiologic, activation of NMDA receptors, it is reportedly well tolerated. A researcher at Forest Laboratories (New York), reported on the effects of memantine in several animal models of acute and chronic neuropathic pain. Memantine inhibited mechanical hyperalgesia in a dose-dependent fashion for up to six hours in rats with painful peripheral neuropathy. Memantine efficacy was 96%, greater than dextromethorphan (65%), MK-801 (34%), and ketamine (18%) administered intrathecally to maximum doses that did not cause motor impairment.

Many anti-epileptic drugs are being used to treat neuropathic pain. Among the latest to be tested in animal models of neuropathic pain is UCB 34714, a pyrrolidone derivative. This drug is structurally related to the antiepileptic drug levetiracetam.

Lamberty and colleagues, in Belgium, compared UCB 34714 and gabapentin in animal models of neuropathic pain. Their results showed that UCB 34714 compared favorably with gabapentin, suggesting that it is a potential new therapy for patients with neuropathic pain.

Some unexpected drugs crop up in the context of pain relief, even in the most rarified of research environments. One is botulinum toxin, BTX more commonly associated with efforts to smooth away the wrinkles of advancing age. There are two subtypes of this toxin, A and B, and both have been used successfully for myofascial pain as well as headaches. It is thought that BTX works via an antinociceptive effect; it may be involved in inhibiting peripheral and central nociceptive processing.

The other unlooked-for analgesic is thalidomide. This drug was banned from use in the 1960s when it produced severe teratogenic effects. However, in 1998, the FDA approved its use for the treatment of debilitating and disfiguring lesions associated with leprosy. Recently, thalidomide has been reported to resolve symptoms of complex regional pain syndrome (CRPS). It appears that thalidomide relieves pain in some patients with recalcitrant CRPS. Further studies are indicated, but because of its potential for causing birth defects, the marketing of thalidomide in the U.S. is tightly controlled by FDA rules. A System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) oversight program has been initiated that includes limiting authorized prescribers and pharmacies, providing extensive patient education about the risks associated with thalidomide, and requiring a 100% patient registry. So thalidomide is unlikely to become a widely used analgesic.

The other aspect of pharmacological pain control that continues to be a focus of research and development activity is drug delivery. The clinical need is twofold. First, many potent analgesics cannot be administered in simple oral formulations; they traditionally have had to be given parenterally, which limits their availability for ambulant patients. Second, even when oral administration is possible, efficacy of pain relief can be compromised by the time taken for the body to absorb and distribute the drug. And there is a third longstanding problem which, perhaps surprisingly, has not yet been entirely overcome: outdated and ill-founded attitudes to administering pain relief. There is still a reluctance in some circles to give potent opiates on demand to patients with severe and unremitting pain. Some medical and nursing staff still feel obliged to ration opiates because of the fear of habituation even in patients whose analgesic need is short-term, for example postoperative cases, and those whose condition is terminal, as in untreatable malignancy.

Patient-controlled anesthesia

It was to address some of these problems that the concept of patient-controlled analgesia (PCA) was developed in the late 1980s. PCA is essentially a bedside facility, and its main use is in postoperative care. The idea is that the patient has an indwelling IV cannula connected to a pump that delivers controlled doses of a powerful analgesic when the patient presses a button. Relief of pain is practically instantaneous, and the pump incorporates a cutout so that the patient cannot dose himself too frequently and so incur the risk of drug cumulation.

PCA hardware has been progressively improved over the past 15 years. The current state of the art is typified by the Abbott Laboratories (Abbott Park, Illinois) PCA Plus II machine. Its features include bolus drug administration, controlled by the patient in response to need; continuous administration mode, set by the clinician to provide ongoing baseline relief; and a combination of both. The drugs are supplied in simply installed unit-of-use syringes, and the machine logs all patient requests, including those that were unsuccessful because they occurred within the cutout period. This helps the clinician to reassess analgesic need, if necessary, and reprogam the machine.

PCA has been shown not only to improve pain control but also to reduce opiate consumption because patient anxiety is diminished and the perceived need for analgesia is correspondingly reduced. However, the clinical context for PCA is very specific and limited; for ambulant patients, and those with chronic pain, other approaches are necessary.

Delivering the goods

In terms of drug delivery, the main improvements in recent years have been in terms of extended absorption after oral administration; transdermal administration by patch; and intranasal delivery. One extended-release analgesic formulation that has been the subject of a recent dose-finding clinical study is oxymorphone ER from Endo Pharmaceuticals (Chadds Ford, Pennsylvania). In a double-blind, placebo-controlled study involving patients with grade II-IV osteoarthritis (hip/knee), doses of 40 mg and 50 mg, given every 12 hours, achieved statistically significant relief. The authors conclude that this formulation provides another option for patients with acute, chronic and cancer pain. An NDA was submitted to the FDA in December 2002, and the filing was accepted in February.

Endo also has developed a transdermal lidocaine patch, marketed as Lidoderm and used to relieve the pain of postherpetic neuralgia, which is a form of neuropathic pain. PHN is often intractable and almost always difficult to treat; typical regimes include anticonvulsants, antidepressants and opioid therapy. The lidocaine patch provides targeted peripheral analgesia for 12 hours at a time and up to three patches may be applied together, according to need.

Innovative Drug Delivery Systems (New York) has developed an intranasal form of ketamine for acute and chronic moderate-to-severe pain, as in breakthrough pain, postoperative pain and pain associated with emergency medical procedures. In a recent presentation, Christensen et al. reported the results of two dose-ranging Phase II studies to evaluate the safety and efficacy of analgesic doses of intranasal ketamine for moderate-to-severe pain in postoperative patients. They used doses of intranasal ketamine ranging from 2.5 mg to 50 mg in a total study population of 80 patients undergoing removal of two to four impacted third molars. At the onset of moderate-to-severe postoperative pain, patients self-administered intranasal ketamine or placebo using a metered spray pump. Intranasal ketamine at doses as low as 10 mg provided a rapid onset (within two to 10 minutes) of analgesia. The authors concluded that intranasal ketamine may offer a safe, nonopiate, analgesic alternative for relief of moderate-to-severe postoperative pain.

Innovative Drug Delivery Systems also has an intranasal morphine product candidate in development. The potential market for these formulations is considerable; the company cites estimates from an independent third-party market research organization, giving estimated fifth-year worldwide sales of the ketamine product as $349 million, and $540 million for the morphine product.

The device approach

In 1962, Smith Kline & French, forerunner to today's SmithKlineBeecham (London), launched a product called Skefron for the relief of musculoskeletal pain. The product was described as a "skin-chilling spray" and the principle behind it was counter-irritation. The theory was that some kinds of pain are self-perpetuating, in that the sensory pain impulses cause a reflex spasm which gives rise to further pain impulses, and so on. The proposed remedy was to interrupt the cycle by providing an alternative stimulus; this was thought to be the basis for the use of rubifacient rubs, which create a sense of warmth and thus "distract" the central nervous system from the pain impulses being received. Skefron achieved its aim via cold, not warmth. There is no scientific literature as to the success of the approach, but in a distant, roundabout way, it was one of the forebears of a technique that has now become universal and well-attested: transcutaneous electrical neural stimulation, or TENS.

TENS consists of the application of low-voltage, biphasic electrical current across the skin over a painful area. The underlying principle is similar (or maybe identical) to counter-irritation. The difference between TENS and simply rubbing on a rubifacient lotion is that TENS technology is highly advanced; various parameters of the applied current can be individually controlled, as well as the area over which it is applied. A wide variety of TENS devices are now available, with a typical cost range of $80 to $120; all are battery-powered and portable (or wearable) to a greater or lesser degree. In the U.S., TENS is available only on a prescription basis, but most healthcare insurance providers cover the cost of TENS devices. In the UK, it is possible to buy a "mini" TENS device intended specifically for the relief of insect stings. Unlike more sophisticated devices, the power for each current spark is provided by pressing a button. Maybe improbably, it does seem to work.

More serious applications for TENS include various musculoskeletal conditions (arthritis, rheumatism, sciatica etc), childbirth, lower back pain, migraine, and other chronic conditions.

The TENS phenomenon has spawned a number of more or less related derivatives. One is MENS, or microcurrent electrical neuromuscular stimulator. It has been theorized that healthy tissue is the result of the direct flow of electrical current throughout the body. Electrical balance is disrupted when the body is injured at a particular site, causing the electrical current to change course. The use of MENS over the injured site is thought to realign this flow, thus aiding tissue repair. In a way, MENS is similar in approach to homeopathic medicine. The latest MENS units deliver a very low voltage current, usually between 1 A and 1000 A. (A microamp ( A) is 1/1000 of a milliamp (mA), so 1000 A equals 1 mA.) Most TENS devices have a milliamplitude of 1-80 mA.

Then there is EMS, electronic muscle stimulation. EMS differs from TENS in that it is designed to stimulate muscle motor nerves, while TENS is designed to stimulate sensory nerve endings. EMS consists of a low volt stimulation targeted to stimulate motor nerves and to cause a muscle contraction. EMS is used mainly by doctors and physical therapists to prevent, or reduce, muscle atrophy after surgery or injuries. Physicians also see EMS as a means of increasing blood flow to muscles, increasing range of motion and increasing muscle strength, as well as enhancing muscle endurance. EMS offers pain management benefits specifically as regards to muscle- related pain, such as a spastic, sore or tight muscles. A TENS device is more suited for nerve-related pain conditions.

The pain sector

There is now a well-defined sector of the medical and pharmaceutical markets specializing in products for the alleviation of pain. Pharmaceutical companies predominate, partly because of the limited scope for medical devices in this field, and partly because the purchase of pain-relieving drugs is repetitive, whereas a single device may last as long as the patient who owns it. In addition to specialist pharma companies, many of the major players also rely on pain-relieving products for a considerable proportion of their sales. Front Line Strategic Consulting (Foster City, California) said in a report issued this past April that the worldwide pain management market is projected to enjoy a 10% overall compound annual growth rate through 2008, reaching a value of $29.8 billion by that time.

Among device-based companies, one prominent entrant is Advanced Neuromodulation Systems (ANS; Dallas, Texas), which manufactures implantable systems used to manage chronic intractable pain and other disorders of the central nervous system. And PainCare Holdings (Orlando, Florida) is a service provider that says it "specializes in the cost-effective delivery of high-tech pain relief through minimally invasive surgery, pain management technologies and orthopedic rehabilitation."