Over-the-Counter Use of Neuroactive Peptides for the Treatment of Chronic Pain

Release Date: December 1, 2010

Expiration Date: December 31, 2012

FACULTY:

Jennifer L. Gibson, PharmD
Marietta, Georgia

FACULTY DISCLOSURE STATEMENTS:

Jennifer L. Gibson, PharmD has no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC, does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-10-045-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To provide an overview of neuroactive peptides and their medical applications, with specific emphasis on patients with pain syndromes.

OBJECTIVES:

After completing this activity, participants should be able to:

  1. Review the historical use of snake venom for the treatment of medical conditions, particularly those requiring pain relief.
  2. Discuss the scientific basis for the use of neuroactive peptides from snake venom for treating physical conditions, such as chronic and acute pain.
  3. Describe the available pain medications that operate according to these mechanisms and review their safety and efficacy data.
  4. Develop patient education strategies about the use of snake venom-based medications for pain relief, particularly over-the-counter (OTC) preparations.

CHRONIC PAIN

Pain control is a complex medical problem, but today physicians and pharmacists have a vast armamentarium of available agents to treat the underlying causes and symptoms of pain. Ideally, the treatment of pain requires an analgesic agent that is potent and effective, safe, and non–habit-forming.1

Acute pain serves as the body’s warning system, responding to disease states and potentially harmful situations. Most cases of acute pain are a result of surgery, acute illness, trauma, or medical procedures. Acute pain is usually nociceptive, arising from tissue or organ damage or disease, but acute pain may also be neuropathic in nature, a result of nerve damage. When acute pain that is the result of an injury or other noxious stimuli does not subside after the normal period of healing, chronic pain may develop, lasting several months or years.1

Chronic pain can be classified as pain that persists beyond the normal healing time for an acute injury, pain related to a chronic disease, pain without an identifiable organic cause, and pain associated with cancer. Like acute pain, chronic pain may be nociceptive or neuropathic, or both.1 The persistent pain can be debilitating and affects a person’s well-being, level of function, and quality of life2 often through the appearance or worsening of depression, insomnia, or family stress.1

Chronic pain may present as sharp, dull, tingling, shooting, or radiating sensations, and may fluctuate in intensity and location.1 Chronic pain often has no objective signs and diagnosis is difficult1,2; it is best diagnosed based on patient history and description.1

Pain extends a great impact on society. Chronic pain is an underestimated and undertreated health care problem that causes substantial decreases in quality of life, as well as burdens on the health care system. An estimated 50 million Americans are partially or totally disabled as a result of pain, and the annual cost of pain in the United States is several billion dollars. As many as one-third of Americans will experience chronic pain in their lifetime and these numbers are expected to rise as patients work and live into older ages.1 Chronic pain is a common factor cited by patients visiting their health care practitioners,3 but the landmark Michigan Pain Study reported that 70% of patients still have pain despite treatment.1

COMPLEMENTARY AND ALTERNATIVE TREATMENTS FOR CHRONIC PAIN

Adequate pain relief is integral to physical and mental health.1 First-line pharmacological treatment for most pain involves acetaminophen, acetylsalicylic acid (aspirin), or nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen or naproxen. Though readily available and relatively inexpensive, these drugs may not be effective for some pain or may cause substantial drug-drug interactions or adverse side effects. Opioids are the most potent pain relievers available, but their use is also limited by individualized responses and adverse effects.1,4 They have short-lived activity and potential unwanted side effects, including dependence,5 so new methods to control pain are of great interest to today’s patients and health care providers.1 Table 1 summarizes the activity and safety of common pain relievers.

Table 1: Comparison of the Analgesic Activity and Safety of Select Oral Pain Relievers
 
DRUG
NAME
ONSET OF
ANALGESIC ACTION
DURATION
OF ANALGESIC
ACTIVITY
POSSIBLE
SIDE EFFECTS1,6-8
Nonopioid Analgesic Agents
Aspirin < 30 minutes 4 to 6 hours Gastrointestinal intolerance, bleeding,
and hypersensitivity
Acetaminophen < 60 minutes 4 to 6 hours Hepatic dysfunction
Ibuprofen 30 to 60 minutes 4 to 6 hours Gastrointestinal intolerance, inflammation,
and bleeding
Naproxen 60 minutes < 7 hours Gastrointestinal intolerance, inflammation,
and bleeding
Opioid Analgesic Agents All Opioid Agents
Morphine (immediate release) 10 to 20 minutes 4 hours Mood changes and lethargy
Hydromorphone
(immediate release)
10 to 20 minutes 4 to 5 hours Drowsiness, nausea, and vomiting
Codeine 10 to 30 minutes 4 to 6 hours Decreased respiration
Methadone 30 to 60 minutes 4 to 8 hours Constipation, urinary retention, urticaria,
pruritus, tolerance, and dependence
Tramadol < 60 minutes 9 hours Dizziness, pruritus, nausea, constipation,
and vomiting
Snake Venom Preparations
Nyloxin, Cobroxin 2 hours to several days up to 24 hours Headache, dry mouth, nausea, vomiting,
dizziness, hemiplegia, palpitations,
and nystagmus

 

Complementary and alternative medicine (CAM) is comprised of a diverse group of medical systems, therapies, and products; information regarding their use is not generally taught to health care professionals. In addition, CAM therapies are not regularly offered by hospitals within the United States,9 though the use of CAM in hospitals is increasing because of patient demand.10 CAM includes, but is not limited to, dietary supplements, such as vitamins, minerals, herbal preparations and botanicals, therapeutic touch, massage, meditation, chiropractic manipulation, yoga, hypnosis, acupuncture, and homeopathy.9 An integrative approach to medicine combines both conventional and CAM therapies to develop customized, holistic solutions for the treatment of various medical conditions. A holistic approach to treating chronic pain is comprehensive and incorporates nutrition, social support, work, exercise, and spiritual histories.3

More than half of the world’s population uses some form of CAM, often in combination with conventional treatments.11 In 2007, 4 out of 10 adults in the United States used some form of CAM, with nonvitamin, nonmineral natural products and deep-breathing exercises chosen most frequently. Similarly, in 2007, 1 out of 9 children used CAM, most often nonvitamin, nonmineral supplements and chiropractic or osteopathic manipulation.12

In the same year, 38.1 million adults made 354.2 million visits to CAM practitioners. In 2007, of the nearly $34 billion Americans spent on CAM, $12 billion accounted for visits to practitioners and $22 billion was for purchases of self-care products, classes, and materials; of the latter, nearly $15 billion was spent on the purchase of nonvitamin, nonmineral natural products.13

The use of CAM for the treatment of chronic pain has increased dramatically within the last 2 decades.10 Pain is among the conditions cited most frequently by CAM users, specifically including back pain, neck pain, joint pain, and stiffness.9,10 In 1997, more than half of the Americans who reported back or neck pain during the year used CAM therapies. CAM use is highest among women, people with higher education, people who have been hospitalized in the previous year, and former smokers.10

HOMEOPATHY

Homeopathy is an independent segment of CAM practices.9,14 It is a distinct domain of medicine that differs from conventional medical practice: homeopathy is one of the holistic disciplines that believes the body possesses innate healing powers.15 The concept for the development of homeopathic medications is based on the principle of like cures like or the law of similars, which states that the same substance causing an ailment in large doses can cure it in small doses.9,14-16

Homeopathy plays a large part in health care systems around the world, but is poorly accepted in the United States because there is a lack of data explaining the mechanism of action for these medications and medical systems.15 Though a controversial practice, homeopathy is frequently used throughout the United States and the world.9,16 The majority of patients who seek homeopathic treatment are experiencing chronic, long-standing conditions, such as pain.16

Sales of homeopathic remedies reached $450 million in the United States in 2003, and sales have experienced a compound annual growth rate of 8% in recent years. Almost 4% of Americans reported using homeopathy in 2003, twice as many people as reported the same 2 decades ago.14

As in other forms of CAM, individualization of treatment is a guiding principle of homeopathy.15 But, unlike herbs and dietary supplements, the U.S. Food and Drug Administration (FDA) regulates the manufacture and distribution of homeopathic medications.14,15 Homeopathic products are subject to the directives of the Federal Food, Drug, and Cosmetic Act (FD&C Act), under the guidance of the FDA, as are all traditional or allopathic products. However, instead of the new drug approval process, homeopathic products are approved by monograph acceptance by the Homoeopathic Pharmacopoeia of the United States (HPUS).14

SNAKES IN MEDICINE

Snakes have been a source of fear and fascination throughout human history.17,18 Snakes have been worshipped, used in ceremonies, and represented in imperial symbols as far back as ancient Egypt, the Holy Roman Empire, and ancient Greece. Still today, the symbols established to represent the professions of medicine and pharmacy incorporate the image of a snake as a means to pay homage to the wisdom and healing powers snakes were believed to possess.17

Snake venom elicits multiple biological responses, including the following: neurotoxic, myotoxic, cardiotoxic, coagulant, hemostatic, edema-inducing, and hemorrhagic.17-20 Snake bites are normally used to immobilize prey18; the signs and symptoms of snake bites include paralysis, myolysis, coagulopathy and hemorrhage, renal damage and failure, cardiotoxicity, and local tissue injury at the bite site.17 Specifically, snake venoms contain a variety of biologically active proteins and peptides, which act on the human hemostatic system and affect the blood coagulation pathway, endothelial cells, and platelets.18,20 Also, neuroactive peptides, or the neurotoxins derived from snake venom, block neuromuscular transmission by reducing acetylcholine (ACh) release.18,19

Early Use of Snake Venoms

Symptoms of a snakebite, or envenomation, suggest that venoms affect multiple organ systems, but the most severe reactions occur in the central nervous system, the muscular system, and the vascular system. In addition to the harmful effects, snake venoms contain potentially therapeutic compounds, including proteins, nucleotides, and inorganic ions. Snake venoms have been used in Ayurveda and folk medicine, as well as homeopathy, for centuries as treatments for a variety of conditions.17 Snake venoms have also been used in allopathic medicine for more than a century to treat thrombosis, arthritis, cancer,18 immune dysfunction, viral infections,5 delirium, hallucinations, chorea, and melancholia.21 At this time, most of the therapeutic use of snake venoms is based on observations or anecdotal reports.4,9

In the mid-1930s, David I. Macht was among the pioneers of research involving the use of snake venoms for medicinal purposes. Macht, a researcher for a pharmaceutical company, outlined the use of cobra venom extracts as an analgesic; his results proved that minute doses of cobra venom were superior to morphine in terms of pain relief. Macht reported that snake venom showed a longer onset of action, but possessed a longer duration of activity, than traditional morphine.22 Similarly, case reports published more than 50 years ago detail the use of small amounts of cobra venom for the treatment of pain related to trigeminal neuralgia.23

Today there are numerous medications and diagnostic tools derived from snake venoms, developed on the basis of the variety of organ systems snake venoms affect, including antihypertensive agents, platelet aggregation inhibitors, fibrinogen inhibitors, and anticoagulants.17,18 Table 2 outlines a few of the countless proteins and compounds with diagnostic and therapeutic potential that have been discovered in the venoms of a variety of snake species.

Table 2: Drugs and Diagnostic Agents Isolated From Snake Venom17,18
 
Drug class or function Examples Source (Common name)
Antihypertensive
Captopril, Enalapril Bothrops jararaca (Brazilian arrowhead viper)
Platelet aggregation inhibitor
Eptifibatide Sistrurus miliarius barbouri (Southeastern pygmy rattlesnake)
Glycoprotein IIb/IIIa inhibitor
Tirofiban Echis carinatus (ocellatus) (West African saw scaled viper)
Fibrinogen inhibitor
Ancrod Agkistrodon rhodostoma (Malayan pit viper)
Thrombin and prothrombin inhibitor
Batroxobin Bothrops moojeni (Brazilian lancehead snake)
Fibrinogenolytic enzymes
Atroxase
Fibrolase
Lebetase
Crotalus atrox (Western diamondback rattlesnake)
Agkistrodon contortrix (Copperhead or moccasin)
Vipera lebetina (Blunt-nosed viper)
Protein C activator Protac Agkistrodon contortrix (Copperhead or moccasin)

 

Mechanism of Action of Neurotoxins

Snake venoms contain high levels of neurotoxins that target nicotinic acetylcholine receptors (nAChRs).24 Neurotoxins are one of the largest families of proteins, and have shown analgesic effects in animal and human pain models.17 Snake venoms contain α- and β-neurotoxins, which act through different mechanisms to block the transmission of ACh.17,24,25 nAChRs have been shown to modulate pain transmission and antinociceptive responses in the central nervous system. The activation of cholinergic pathways by nicotinic receptor antagonists decreases the perception of pain in a variety of species.26

α-Neurotoxins

α-Neurotoxins act postsynaptically and bind to nAChRs.17,25 They act as nicotinic receptor antagonists27 by competitively binding to the nAChR at the postsynaptic membrane of skeletal muscles and neurons, thereby reversibly blocking nerve transmission. The major groups of α-neurotoxins include short-chain neurotoxins, long-chain neurotoxins, and weak neurotoxins.17 Short-chain neurotoxins have between 60 and 62 amino acid residues and 4 disulfide bonds; long-chain neurotoxins have between 66 and 74 residues and 5 disulfide bonds.25 Weak neurotoxins are isolated from cobra venom and, as the name suggests, have very weak affinity for skeletal and neuronal nAChRs.17

Cobrotoxin: Cobrotoxin is a short-chain postsynaptic α-neurotoxin.17,25 This compound is isolated from the Naja naja atra, the Chinese or Taiwan Cobra.25 Cobrotoxin has high affinity for the muscle-based α1 subunit of the nAChR17; however, it also produces strong, centrally mediated analgesia via an opiate-independent mechanism in rodents.5,17,25 When evaluated in rodent pain models, cobrotoxin exhibited substantial antinociceptive effects. Cobrotoxin was administered via intraperitoneal injection (33.3, 50, or 75 µg/kg), intracerebral-ventricular injection (2.4 µg/kg), or as a microinjection into the periaqueductal gray (1.2 µg/kg). The effects of cobrotoxin were assessed via the hot-plate test and the acetic acid writhing test. Results indicated that intraperitoneal administration produced dose-dependent analgesia and injection into the cerebral-ventricle or the periaqueductal gray similarly produced marked analgesia among the rodents. In addition, neither atropine nor naloxone blocked the effects of cobrotoxin, suggesting that their mechanism of action is not opioid-based.25

There is limited evidence to suggest that cobrotoxin can act as a morphine substitute to mitigate morphine withdrawal symptoms, as well.17 Cobrotoxin is already commercially available in China as an analgesic.5

Cobratoxin: Cobratoxin is a long-chain postsynaptic α-neurotoxin,4,5 composed of 71 amino acids.24 The structure of cobratoxin is characteristic of long-chain neurotoxins: the polypeptide chain is organized into 3 major loops, resembling fingers radiating from a knotted palm of disulfide bonds. Cobratoxin is isolated from the Naja kaouthia, the Thailand Cobra, and it has substantial affinity for the neuronal α7 subunit of the nAChR (α7nAChR), which is predominantly located in the peripheral nervous system. The α7nAChR also exhibits high-affinity to sites within the brain. In addition, the α7nAChR regulates calcium ion channels. Activation by cobratoxin leads to the depolarization of postsynaptic membranes and the prevention of neurotransmitter release. It is believed that the α7nAChR mediates the antinociceptive and anti-inflammatory actions of cobratoxin.24

Owing to its anti-inflammatory and antinociceptive mechanisms, cobratoxin modulates the production of inflammatory cytokines and has analgesic properties in animals. According to rat models of rheumatoid arthritis, cobratoxin (17 µg/kg intraperitoneal injection) substantially reduced paw swelling and hyperalgesia and decreased circulation of the following inflammatory cytokines: tumor necrosis factor-α, interleukin-1, and interleukin-2.24 Similar to cobrotoxin, the antinociceptive effects of cobratoxin were evaluated in rodent models, using the acetic acid writhing test and the hot-plate test. Cobratoxin was administered via intraperitoneal injection (30, 45, or 68 µg/kg), intracerebral-ventricular injection (4.5 µg/kg), or as a microinjection into the periaqueductal gray (4.5 µg/kg). The intracerebralventricular administration of cobratoxin produced marked analgesia according to the acetic acid writhing test; however, microinjection into the periaqueductal gray did not produce analgesia according to the hot-plate test.5 The effects of cobratoxin are opiate-independent. Atropine affects the activity of cobratoxin, but naloxone does not.24

β-Neurotoxins

β-neurotoxins isolated from cobra venoms exhibit phospholipase activity.25 The β-neurotoxins act presynaptically and affect the release of ACh through a variety of mechanisms, including causing the disappearance of ACh-containing vesicles, which prevents the release of ACh and blocks impulse transmission. In nature, β-neurotoxins demonstrate high toxicity and are responsible for respiratory paralysis after envenomation.17

Crotoxin: Crotoxin is a potent phospholipase A2 (PLA2) neurotoxin. PLA2 neurotoxins from snake venom are highly specific β-neurotoxins that inhibit the release of ACh from peripheral synapses28; they interfere with the normal biological processes through a variety of pharmacological effects, including anti-inflammatory and antineoplastic effects. Accordingly, crotoxin is a presynaptic neurotoxin with cytotoxic activity.17 It also works postsynaptically and stabilizes the ACh receptor in an inactive or desensitized state.27 Crotoxin is the major protein component of the venom of the South American rattlesnake, Crotalus durissus terrificus,5,25 and was the first snake venom protein to be purified and crystallized.29 It is composed of 2 subunits, a weak toxic PLA2 subunit and a nonenzymatic, nontoxic subunit.19,30

Crotoxin’s classic biological activity includes neurotoxic, myotoxic, nephrotoxic, and cardiotoxic effects.29 It also possesses immunomodulatory, anti-inflammatory, antimicrobial, antitumor, and analgesic actions.29,31 Crotoxin continues to be evaluated in cancer research5,17 because of its antinociceptive and antitumor effects.25 It also demonstrates synergism with acetylsalicylic acid.5 Like other neurotoxins isolated from snake venoms, muscarinic and opioid receptors are not involved in the effects of crotoxin. The analgesic effects of crotoxin are mediated by activity in the central nervous system.31

Crotamine and Crotalphine

Crotamine and crotalphine, also isolated from the venom of the Crotalus durissus terrificus, have recently been identified to have antinociceptive activity. The effects of crotamine were inhibited by naloxone in mice, suggesting an opioid-based mechanism. At low doses, crotamine was reported to be 30 times more potent than morphine.32 Crotalphine also exhibits an opioid-dependent mechanism and its duration of analgesia outlasted other traditional pain relievers.4

NEUROTOXINS IN THE TREATMENT OF PAIN

Clinical Safety and Efficacy of Snake Venom Extracts
In general, randomized, controlled trials investigating the use of homeopathic remedies to treat chronic pain are lacking. Though studied extensively in rodent populations, relatively few human studies have been conducted involving the use of snake venom extracts, and those that have are of short duration, have small patient populations, or have methodological shortcomings.9 However, a few notable studies have evaluated the safety and efficacy of snake venom extracts for the treatment of pain in human populations.

Zhu and Liu33 evaluated the safety and efficacy of purified cobra neurotoxin in 92 acute and chronic pain cases. The extract was injected at doses of 70 µg/day for 5 days. The total effective curative rate was nearly 97%; the onset of analgesia was 30 to 60 minutes after injection; and the pain relief lasted 6 to 10 hours. The most severe side effects experienced by study participants were dry mouth and dizziness. The authors reported that cobra neurotoxin was a useful substitute for potentially addictive pain medications, like opioids.33

Wang, Wang, and Hu34 evaluated the effectiveness of cobratoxin as postoperative analgesia. In total, 72 patients were administered an epidural block during surgical procedures. The patients were then divided into 4 equal groups and investigators compared the effectiveness of 2 different doses of cobratoxin, morphine, and lidocaine for pain relief. The periods of analgesia for the patients receiving either dose of cobratoxin were substantially longer than that of other modes of analgesia. Specifically, patients who received cobratoxin 0.25 µg/kg experienced 412±25 minutes of pain relief as compared with those receiving cobratoxin 0.125 µg/kg, who experienced 345±28 minutes of relief. No side effects were observed among the patients receiving cobratoxin.34

A cobrotoxin-containing oral combination product, compound Keluoqu, has also been evaluated for pain control. The formulation contains cobrotoxin (0.16 mg), tramadol hydrochloride (25 mg), and ibuprofen (50 mg).35 Xu et al36 evaluated the effectiveness of Keluoqu for the treatment of cancer pain as compared with the effectiveness of either 50 mg of tramadol or placebo. Two studies included 230 patients: 119 patients were randomized to a double-blind crossover study and 111 to an open-label study. In the crossover study, the overall pain relief rate with the cobrotoxin-containing compound was nearly 84%, substantially higher than the pain relief achieved with tramadol alone (68.2%) or placebo (35.1%). Of the 35 patients who did not respond to tramadol, 27 (77.1%) of them did achieve pain relief with cobrotoxin. For patients who achieved pain relief with the cobrotoxin-containing compound, the duration of pain relief was substantially longer than other pain relievers. In the open-label arm, the overall relief rate after the first dose of the cobrotoxin compound was 89%.36

A similar open-label study involving Keluoqu reported a 93% rate of effectiveness after the first dose, with the average onset of pain relief occurring after 35 minutes and lasting for a duration of more than 6 hours.37 In these open-label studies, both a decrease in total pain relief and an increase in partial pain relief was seen with the continuous administration of 10 doses of the cobrotoxin-containing compound.36,37 No substantial difference in efficacy was observed in patients with either moderate or severe pain, but the onset of activity was quicker and the duration of action shorter for patients with severe pain.37 In all studies, the side effects experienced with Keluoqu were similar to the side effects observed after the use of tramadol, which include the following: nausea, dizziness, and fatigue.36,37

Xu et al38 also conducted a randomized, double-blind, placebo-controlled trial comparing the effectiveness of Keluoqu with that of placebo for postoperative pain. Of the 101 patients in the study, 91% achieved pain relief versus 19% of those administered a placebo. The onset of pain relief did not differ among the treatment and control groups (35 minutes versus 38 minutes, respectively), but the duration of pain relief was substantially longer for the patients receiving the cobrotoxin-containing compound (6.5 hours) as compared with those receiving placebo (2.9 hours). In this study, Keluoqu was administered by both oral administration and sublingual administration, but the responses were nearly equal regarding the onset and the duration of pain relief. The only substantial difference between the 2 forms of administration was the time to peak relief, which was 55.1 minutes for sublingual administration and 60.8 minutes for oral administration. The side effects of cobrotoxin were nausea, dizziness, hypodynamia, palpitations, and sweating, which occurred more frequently than they did in the control group, but patients reported that the side effects were tolerable.38

Crotoxin was evaluated in a Phase 1 clinical trial involving patients with advanced cancer. In total, 23 patients received crotoxin, administered intramuscularly for 30 consecutive days. The dose of crotoxin escalated throughout the study, according to patient response, and ranged from 0.03 to 0.22 mg/m2. Eighteen of the patients reported either a substantial decrease or the disappearance of pain while receiving crotoxin, which was assessed by patient reports and an observed reduction in the use of traditional analgesics. Neurotoxicity, including nystagmus, palpebral ptosis, and anxiety, was the most significant side effect seen with crotoxin, but the effects were manageable. Myotoxicity also occurred, as evidenced by transient increases in the levels of creatine kinase, aspartate aminotransferase, and alanine transaminase; the levels of these enzymes returned to normal before the end of the study period.39

This Phase 1 trial also evaluated the pharmacokinetic properties of crotoxin in humans. The venom exhibited a 2-compartment open model, with first-order distribution. After injection, the absorption of crotoxin was rapid and complete, with a half-life of 22±3 minutes. The half-life of elimination was 5.2±0.6 hours, indicating that > 95% of the neurotoxin was eliminated within 24 hours of administration. Crotoxin is excreted by the urine. The bioavailability of crotoxin was approximately 1 and the volume of distribution was 12±3 L/kg.39

These findings are similar to the pharmacokinetic properties of snake venoms in animal models. After intravenous administration, the α-neurotoxins found in cobra venoms demonstrated complete and rapid distribution. The half-life of elimination ranged from 15 to 29 hours and the toxin was detectable in the animal between 20.8 and 51.8 hours after administration.7,8

AVAILABLE SNAKE VENOM PRODUCTS

Recently, 2 products containing neuroactive peptides from snake venom have become available in the United States for the treatment of pain. Marketed as Nyloxin and Cobroxin, these over-the-counter (OTC) pain relievers contain a purified extract from the venom of the Asian cobra, Naja tripudians. These homeopathic products are indicated for use in the treatment of angina fauces, angina pectoris, asthma, painful menses, hay fever, depression, headache, ovarian cysts, plague, back pain, and sore throat, in addition to other forms of pain.7,8

A description of the mechanism of action for these medications is not complete at this time, but the venom extract likely exhibits postsynaptic α-neurotoxin and presynaptic β-neurotoxin activities. The products are classified as anticholinergic, in terms of pharmacological action.7,8

As evidenced in some of the clinical studies, the onset of pharmacological activity from venom neurotoxins is slower than traditional NSAIDs or opiate pain relievers; there could be a difference of several hours, according to the manufacturers of Nyloxin and Cobroxin. In fact, effective pain relief may not be reached until several days of therapy with cobra venom extracts, especially when using the oral pain reliever sprays. The topical formulations demonstrate the quickest onset of action in areas where skin is thin and in areas where there is little muscle. However, snake venom extracts exhibit a duration of pain relief more prolonged than traditional analgesics (Table 1), which could present a substantial benefit for patients requiring long-term pain relief.7,8

Indications for the use of these medications, according to the manufacturers of Nyloxin and Cobroxin, include results from studies involving rodent models, which indicate that the effects of camphor, borneol, atropine, nikethamide, pentylenetetrazol, picrotoxin, phenol, absinthe, and caffeine were antagonized by the concomitant administration of cobra venom extracts. Also, the toxic effects of morphine and cobra venom are additive. In addition to these findings, it has been reported that cobra venom interacts negatively with nicotine, vitamin B12, and azathioprine; cobra venom extracts may lower blood pressure. Most of the adverse effects associated with the administration of snake venoms are mild and transient and are related to the neurotoxic effects, which may include any the following: headache, nausea, vomiting, dry mouth, dizziness, sweating, palpitations, diplopia, nystagmus, and hemiplegia.7,8

Patients with a history of allergy to snake venoms should not use Nyloxin or Cobroxin. Anaphylaxis has been reported after the administration of snake venom, but the use of antihistamines has alleviated the symptoms. Generally, Nyloxin and Cobroxin OTC products are considered safe and nontoxic and do not encourage dependence in users.7,8

Nyloxin and Cobroxin are available for the treatment of moderate-to-severe chronic pain7,8; Nyloxin also has extra strength formulations available for severe chronic pain.7 Both Nyloxin and Cobroxin products are available in relatively low-potency formulations, ranging from 4X to 8X for Nyloxin products7 and from 4X to 5X for Cobroxin products.8 (See Sidebar 1 for a definition of homeopathic potencies.) These homeopathic potencies correspond to approximately 30 to 60 µg/mL of active venom extracts for topical formulations and 70 to 140 µg/mL for oral sprays. Topical formulations of these products, available as bottles, pumps, or roll-on applicators, can be used on an as-needed basis when applied directly to the site of pain. Oral sprays, flavored orange and sweetened with xylitol, are initially dosed at 2 sprays every 4 to 6 hours. The frequency and dose may be reduced when maximum pain relief has been achieved.7,8

Sidebar 1: Homeopathic Potency15
 

The potencies of homeopathic products are defined
    in terms of dilutions.

The letter X is used in the United States to designate
    a 1:10 dilution.

For example, 1X = 1:10 dilution, 2X = 1:100 dilution,
    3X = 1:1000, etc.

The letter C is used in the United States to designate
    a 1:100 dilution.

For example, 1C = 1:100, 2C = 1:10,000,
    3C = 1,000,000, etc.

A higher potency will refer to more dilute preparations
    than a lower potency.

For example, 2X is more potent than 1X.

 

There is currently no research investigating the use of Nyloxin and Cobroxin in pediatric or young-adult populations. Additionally, there are no safety data regarding the use of snake venom products during pregnancy or lactation.7,8

PATIENT EDUCATION

Any recommendation or treatment plan for chronic pain – whether allopathic or homeopathic – should be designed to reduce pain, restore function, and improve quality of life. Patients should be educated about the possible side effects and warned about the drug-drug interactions of the products available on the market today. Health care professionals should also assist patients by frequently monitoring the effectiveness of any pain relief regimen, which is necessary to achieve optimal pain relief.2

For any homeopathic product or OTC medication, patients should be instructed to follow the dosing guidelines provided by the manufacturer. These guidelines should never be exceeded, except under the supervision of a specialized health care professional. Also, patients should be advised not to change their current medication regimens, including decreasing or discontinuing doses of prescription or OTC medications, without first consulting with a physician or pharmacist. Though rare, patients should seek medical attention in the case of a severe or life-threatening reaction to a homeopathic product. As with all drugs, homeopathic products should be stored out of the reach of children. In addition, pharmacists should encourage patients to maintain a list of their current medications and instruct them to have this list available at all times. The medication list should include all prescription, OTC, and homeopathic medicines, as well as the vitamins, minerals, and herbal supplements they are taking.15

ROLE OF THE PHARMACIST

As an easily accessible and often trusted health care professional, pharmacists must be able to counsel patients about the safe and effective use of all medications, including CAM and homeopathic remedies.11 However, most pharmacists have a considerable lack of training in regard to CAM11 and pain management,1 which poses a barrier to providing accurate information to patients. Also, most clinical trials conducted involving homeopathy, and snake venoms in particular, have been conducted in Asian countries, often making the accessibility and dissemination of these reports difficult.15 Fortunately, education regarding the benefits and limitations of CAM has been increasingly incorporated into the curricula of conventional institutions for clinical education in the United States; this has become especially true for evidence-based practice, which provides the perfect stage for future physicians and pharmacists to gain inclusive knowledge of once-unconventional treatments.11

Today’s pharmacists may not be formally educated about homeopathic remedies, but educational resources are available to assist both health care professionals and patients with gaining information regarding the best possible comprehensive and customized care. Sidebar 2 summarizes some of the available journals and organizations that pharmacists may contact for further information about homeopathy practices and remedies. Pharmacists must learn new paradigms to analyze and develop care plans for patients using homeopathic remedies. In fact, homeopathic remedies may be a suitable alternative for pharmacists and patients concerned about the overuse of antibiotics or analgesics, as well as the long-term safety and efficacy of conventional drugs.15

Sidebar 2: Resources for Additional Information14,15
 
JOURNALS

The American Homeopath: Journal of the North American Society of Homeopaths (NASH).
www.homeopathy.org

Homeopathy Today: Journal of the National Center for Homeopathy (NCH).
www.homeopathytoday.org

The New England Journal of Homeopathy
: Journal of the Foundation for Homeopathic Education,
New England School of Homeopathy (NESH). www.nesh.com

Simillimum: Journal of the Homeopathic Academy of Naturopathic Physicians (HANP).
www.hanp.net/ simillimum/about

WEB SITES

www.chedu.org: Web site of the Council on Homeopathic Education (CHE)
www.homeopathic.org: Web site of the National Center for Homeopathy (NCH)
www.homeopathicpharmacy.org: Web site of the American Association of Homeopathic Pharmacists (AAHP)
www.hpus.com: Web site of the Homoeopathic Pharmacopoeia of the United States (HPUS)

 

Chronic pain management is most effective when a multidisciplinary approach is used.1 Pharmacists and other traditional health care providers should be proactive in communicating with patients about the use of CAM, identifying patients’ needs, and involving them in the decision-making process.10

REFERENCES

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