THE BIOCHEMICAL ORIGIN OF PAINby Sota Omoigui

CHAPTER 9

NEW BREAKTHROUGH TREATMENT OPTIONS FOR PERSISTENT PAIN

Botulinum Toxin
Etanercept
Infliximab
Anakinra
Leflunomide
Pentoxifylline
Clarithromycin
Tetracyclines
Ondansetron
DMSO
Pamidronate
Protriptyline
Oxcarbazepine
Thalidomide
Nerve Blockade
Surgery

Anti-Spasm Medications

BOTULINUM TOXINS (BOTOX, MYOBLOC)

Botulinum toxins are potent nerve toxins, which bind to transport proteins in nerve cells and block the release of nerve transmitters from nerve endings. One of these transmitters called acetylcholine is released by nerve cells and transported into muscle cells to signal the muscle to contract. Blockade of this transmitter by Botulinum toxin can produce a long lasting relief of muscle spasms. By interfering with transport proteins in nerve cells, studies have shown that Botulinum toxin may also inhibit the release of excitatory nerve transmitter glutamate [95] and inflammatory mediators such as Arachidonic acid (AA) [96] , vasoactive intestinal peptide (VIP) and Neuropeptide Y (NPY)[97] . Botulinum toxins also inhibits the release of tumor necrosis factor alpha [98] [45] (TNF-alpha) from immune cells and thus can alleviate pain and spasm produced by the inflammatory response..

INFLAMMATORY MEDIATOR BLOCKER MEDICATIONS

Tumor Necrosis Factor Alpha Blocker Medications
The central role in inflammatory responses have InterLeukin-1 and TNF-alpha because the administration of their antagonists, such as IL-1ra (Interleukin-1 receptor antagonist), soluble fragment of Interleukin-1 receptor, or monoclonal antibodies to TNF-alpha and soluble TNF receptor, all block various acute and chronic responses in animal models of inflammatory diseases.

ETANERCEPT (ENBREL)

Etanercept is a fusion protein produced by recombinant DNA technology. Etanercept binds to and inactivates Tumor Necrosis Factor (TNF-alpha) but does not affect TNF-alpha production or serum levels. Etanercept may also modulate other biologic responses that are induced or regulated by TNF-alpha such as production of adhesion molecules, other inflammatory cytokines and matrix metalloproteinase-3 (MMP-3 or stromelysin). Patients with rheumatoid arthritis have increased levels of TNF-alpha in their joint fluid. The introduction of Etanercept transformed the treatment of rheumatoid arthritis. Etanercept decreases the inflammation and inhibits the progression of structural damage in patients with moderately to severely active rheumatoid arthritis. When Etanercept was added in patients who had persistent disease despite receiving Methotrexate, rapid and sustained improvement was noted. Etanercept has been used successfully in the treatment of other inflammatory disorders. In one study, TNF-alpha blockade with Etanercept was markedly effective in controlling the clinical manifestations of inflammatory back pain located in the cervical spine, lumbar spine and sacro-iliac joints [99] [67]. In another study, Etanercept was found to reduce pain and hyperalgesia in an animal model of painful neuropathy. Treatment with Etanercept by local near-nerve injection to the injured nerve or by systemic application significantly reduced thermal hyperalgesia and mechanical hypersensitivity to pain. The effect of Etanercept was present in animals that were treated from the time of surgery and in those that were treated from day 6, when hypersensitivity to pain was already present. The authors conclude that the results suggest the potential of Etanercept as a treatment option for patients with neuropathic pain [100][68]. In another research study, two tumor necrosis factor-alpha inhibitors (Etanercept and Infliximab) prevented the reduction of nerve conduction velocity and nerve fiber injury produced by application of disk tissue (nucleus pulposus) to a nerve [101] [69].

INFLIXIMAB (REMICADE)

Infliximab is a monoclonal antibody targeted against tumor necrosis factor-alpha (TNF-alpha). Infliximab neutralizes the biological activity of the cytokine tumor necrosis factor-alpha (TNF-alpha). Infliximab binds to high affinity soluble and transmembrane forms of TNF-alpha and inhibits the binding of TNF-alpha with its receptors. Infliximab does not neutralize TNF-beta, a related cytokine that utilizes the same receptors as TNF-alpha. Biological activities attributed to TNF-alpha include induction of pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6; enhancement of leukocyte migration by increasing endothelial layer permeability; expression of adhesion molecules by endothelial cells and leukocytes; activation of neutrophil and eosinophil functional activity; fibroblast proliferation; synthesis of prostaglandins; and induction of acute phase and other liver proteins. In patients with rheumatoid arthritis, infliximab substantially improves clinical symptoms when given in combination with Methotrexate. In patients with rheumatoid arthritis, infliximab treatment reduces inflammatory cell infiltration into inflamed areas of the joint and reduces the expression of molecules mediating adhesion [E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vacular adhesion molecule-1 (VCAM-1)], chemoattraction (monocyte chemotactic protein (MCP-1 and IL-8), and tissue degradation (matrix metalloproteinase (MMP) 1 and 3). In patients with Crohn’s disease, infliximab reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas of the intestine. In addition, the proportion of mononuclear cells from the lamina propria able to express TNF-alpha and interferon gamma is reduced. After treatment with infliximab, patients with Crohn’s disease or rheumatoid arthritis have decreased concentrations of IL-6 and C-reactive protein as compared to baseline.

ANAKINRA (KINERET)

Anakinra is a form of the human interleukin-1 receptor antagonist (IL-1Ra) produced by recombinant DNA technology. Anakinra differs from the naturally occurring native human IL-1Ra in that it has an additional methionine residue at its amino terminus. Anakinra acts similarly to the naturally occurring interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra blocks effects of Interleukin-1 by competitively inhibiting binding of this cytokine, specifically IL-alpha and IL-beta, to the interleukin-1 type 1 receptor (IL-1R1), which is produced in a wide variety of tissues. Il-1Ra is part of the feedback loop that is designed to balance the effects of inflammatory cytokines. During clinical trials, rheumatoid arthritis patients treated with Anakinra experienced clinical responses, including improvement in swollen and painful joints within 4 weeks, and most by 13 weeks, of therapy. After 6 months of therapy, 38% of patients treated with Anakinra, alone or in combination with Methotrexate, achieved a 20% improvement in the American College of Rheumatology criteria.

LEFLUNOMIDE (ARAVA)

Leflunomide interferes with RNA and protein synthesis in immune T and B-lymphocytes. T and B cell collaborative actions are interrupted and antibody production is suppressed. Leflunomide is the first agent for rheumatoid arthritis that is indicated for both symptomatic improvement and retardation of structural joint damage. Leflunomide may also have anti-inflammatory properties secondary to reduction of histamine release, and inhibition of induction of cyclooxygenase-2 enzyme (COX-2). Leflunomide may decrease proliferation, aggregation and adhesion of peripheral and joint fluid mononuclear cells. Decrease in the activity of immune lymphocytes leads to reduced cytokine and antibody-mediated destruction of joints and attenuation of the inflammatory process.

PHOSPHODIESTERASE INHIBITOR MEDICATION

PENTOXIFYLLINE

Pentoxifylline is a phosphodiesterase inhibitor, which is used as a blood thinner medication in persons who have poor peripheral circulation. However the drug has another unique effect. It suppresses inflammatory cytokine production by T cells and macrophages [102] [46]. Some of the anti-inflammatory effects occur by blocking nitric oxide (NO) production by macrophages. Pentoxifylline also blocks the production of Tumor Necrosis Factor Alpha. In one study, Pentoxifylline prevented nerve root injury and swelling (dorsal root ganglion compartment syndrome) caused by topical application of disk tissue (nucleus pulposus) [103] [47]

ANTIBIOTIC MEDICATION

CLARITHROMYCIN (BIAXIN)M

Studies have shown that injured joint cells produce cytokine inflammatory mediators including IL-1beta, IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF. Clarithromycin significantly inhibits the production of these cytokines and also suppresses the proliferation of immune T cells [104] [48].

TETRACYCLINES (DOXYCYCLINE, MINOCYCLINE)

Tetracyclines such as doxycycline and minocycline may block a number of cytokines including Interleukin-1 [105] [49] [106] [50], IFNg [107] [51], NO-synthetases, and metalloproteinases [108] [52]. Interleukin -1 and IFN-.gamma act synergistically with TNF-alpha and are known to be toxic to nerve tissue [109] [53] [110] [54] [111] [55] [112] [56] [113] [57]. One study showed that oral administration of doxycycline prevented the breakdown of cartilage in subjects with osteoarthritis [114] [58]. In another study, a patient with rheumatoid arthritis who did not respond to other arthritis medications had marked improvement with Minocycline [115] [59]. In another study, minocycline-treated patients were more likely to have gone in remission and discontinued treatment with prednisone at 2 years than patients who were treated with other standard rheumatoid arthritis medications [116] [60]. Tetracyclines may also block the inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-alpha). Tumor Necrosis Factor Alpha is released by herniated disk tissue (nucleus pulposus), and is primarily responsible for the nerve injury and behavioral manifestations of experimental sciatica associated with herniated lumbar discs [117] [61]. In one study, treatment with doxycycline significantly blocked the nucleus-pulposus-induced reduction of conduction velocity [118] [62

ANTI-NAUSEA SEROTONIN (5-HT3) BLOCKERS

ONDANSETRON (ZOFRAN)

In migraine, 5-HT3-receptor antagonists show moderate efficacy, as well. Repeatedly demonstrated efficacy of 5-HT3-receptor antagonists such as Tropisetron in patients suffering from fibromyalgia raises the question for the mechanism of action involved. Ligand binding at the 5-HT3-receptor causes manifold effects on other neurotransmitter and neuropeptide systems. In particular, 5-HT3-receptor antagonists diminish serotonin-induced release of substance P from C-fibers and prevent unmasking of NK2-receptors in the presence of serotonin. These observations possibly provide an approach for the causal explanation of favorable treatment results with 5-HT3-receptor antagonists in fibromyalgia [119] [63].

FREE RADICAL SCAVENGER MEDICATIONS DMSO

(Dimethyl sulfoxide)
A scavenger of oxygen radicals, topical DMSO inhibits nerve conduction and decreases inflammatory swelling. DMSO local anti-inflammatory effects provide symptomatic relief when the solution is applied in the bladder (intra-vesically) in patients with interstitial cystitis. A crossover study was performed for patients with RSD/CRPS to evaluate the therapeutic efficacy of the hydroxyl radical scavenger DMSO. All patients were given DMSO locally 5 times a day during one week, and a placebo during one week. Before and after each treatment, both the patient and the examiner performed subjective evaluation of the clinical activity of RSD/CRPS. Measurement was then performed of the range of motion (ROM) of all joints in the affected extremity. DMSO was the most effective treatment as to improvement of ROM (p = 0.035) and as to overall improvement (p = 0.001). The authors concluded that the efficacy of the hydroxyl radical scavenger DMSO indicates that RSD/CRPS primarily involves an inflammatory process rather than a sympathetic reflex. The authors further stated that during the last 20 years no single report was published studying RSD in terms of inflammation. The authors then suggested that such studies are urgently needed to elucidate the real nature of RSD/CRPS [120] [64]

BISPHOSPHONATE BONE BUILDER MEDICATIONS

ALENDRONATE, PAMIDRONATE (FOSAMAX, AREDIA)

Bisphosphonates originally were used to soften hard water. This class of drugs reduces bone turnover and bone loss. Like other organs with a blood supply, the bones also react to the disturbances in permeability caused by various inflammatory mediators. There is fluid accumulation in the bones and loss of bone density (osteoporosis) [121] [65]. In addition, the inflammatory mediators accelerate the rate at which bone is broken down. The bone loss is further aggravated by decreased use of the affected body part due to pain. Bisphosphonates are used in the treatment of bone pain due to Paget’s disease, postmenopausal osteoporosis, bone metastasis in patients with advanced cancer and in the treatment of elevated calcium levels associated with cancer. In one study, the efficacy and the safety of Pamidronate was assessed in patients in various stages of recalcitrant reflex sympathetic dystrophy (RSD/CRPS). Some patients had more than one site involved. Mean duration of the disease was 15 months. About half of the patients have been previously treated unsuccessfully by sympathetic blockades. Pamidronate was administered intravenously for 1- 3 consecutive. Efficacy was assessed by a decrease of pain. A significant decrease of pain was observed. These results suggest an efficacy of Pamidronate in recalcitrant RSD [122] [66].

Solid cancers metastasize to bone by a multi-step process that involves interactions between tumor cells and normal host cells. Some tumors, most notably breast and prostate carcinomas, grow avidly in bone because the bone microenvironment provides a favorable soil. In the case of breast carcinoma, the final step in bone metastasis (namely bone destruction) is mediated by osteoclasts that are stimulated by local production of the tumor peptide parathyroid hormone-related peptide (PTH-rP), whereas prostate carcinomas stimulate osteoblasts to make new bone. Production of PTH-rP by breast carcinoma cells in bone is enhanced by growth factors produced as a consequence of normal bone remodeling, particularly activated transforming growth factor-beta (TGF-beta). Thus, a vicious cycle exists in bone between production by the tumor cells of mediators such as PTH-rP and subsequent production by bone of growth factors such as TGF-beta, which enhance PTH-rP production. The metastatic process can be interrupted either by neutralization of PTH-rP or by rendering the tumor cells unresponsive to TGF-beta, both of which can be accomplished experimentally. The osteoclast is another available site for therapeutic intervention in the bone metastatic process. Drugs such as the new-generation bisphosphonates can inhibit osteoclasts; as a consequence of this inhibition, there is a marked reduction in the skeletal events associated with metastatic cancer to bone, such as pain, fracture, and hypercalcemia. However and possibly even more importantly, there is also a reduction of tumor burden in bone. In experimental situations, this has clearly been shown to affect not only morbidity but also survival. The precise mechanism by which bisphosphonates inhibit osteoclasts is still unclear and may represent a combination of inhibition of osteoclast formation as well as increased apoptosis in mature osteoclasts. However, studies with potent bisphosphonates such as ibandronate, pamidronate, and risedronate have clearly documented that reduction of bone turnover and osteoclast activity leads to beneficial effects not only on skeletal complications associated with metastatic cancer, but also on tumor burden in bone [123] . In conclusion, Bisphosphonates not only reduce bone complications and related pain, thereby improving quality of life, but also may have intrinsic anti-tumor activity by virtue of inducing tumor cell adherence to marrow, reducing interleukin-6 secretion, inducing tumor cell apoptosis, or inhibiting angiogenesis [124] .

ANTI-DEPRESSANT MEDICATIONS

PROTRIPTYLINE (VIVACTIL)
2000 years ago, St John’s wort, a herbal anti-depressant was used to treat sciatic and nerve pain. Studies have shown that it is only the older tricyclic class anti-depressants like protriptyline or desipramine that are effective in the treatment of persistent pain. Newer SSRI class anti-depressants like Prozac and Paxil are not effective. The analgesic effects of Protriptyline and other cyclic type antidepressants may occur partly through the alleviation of depression, which may be responsible for increased pain suffering, but also by mechanisms that are independent of mood effects. Current research suggests that the pain-relieving effect of antidepressants is due to their blockade of reuptake of chemical transmitters norepinephrine and serotonin. The resulting increase in the levels of these chemical transmitters enhances the activation of pain inhibiting pathways that descend from the brain to the spinal cord. Activation of these pathways decreases the transmission of pain impulses from injured or inflamed nerves to the spinal cord dorsal horn wherein the impulses are transmitted to the brain. Amitriptyline and other cyclic antidepressants may also enhance the analgesic effect of opioid medication by increasing their efficacy of binding to opioid receptors. Protriptyline (and other cyclic antidepressants) may have a blocking effect on spinal N-methyl-D-aspartate (NMDA) receptors, and inhibit NMDA receptor activation-induced neuroplasticity [125] [70]. Spinal NMDA receptor activation is believed to be central to the generation and maintenance of persistent hyperalgesic pain. Anti-depressant medication may also have effects on inflammatory mediators. In one study, four weeks of prolonged administration of amitriptyline and desipramine resulted in a significant increase in the secretion of the anti-inflammatory cytokine Interleukin-10[126] [71].

ANTI-SEIZURE MEDICATIONS

OXCARBAZEPINE (TRILEPTAL)

Subsequent to tissue injury, the expression of sodium channels in nerve fibers is altered significantly thus leading to abnormal excitability in the sensory neurons. Studies have shown that the inflammatory mediators interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist and inducible nitric oxide synthetase are significantly increased when there is excessive nerve traffic as occurs during seizures or persistent pain [127][72]. Anti-seizure medications such as Trileptal or Zonegran decrease pain by reducing the rate of continuing discharge of injured and inflamed nerve fibers. Blockade of sodium channels in nerve cells leads to a decrease in electrical activity and a subsequent reduction in release of the excitatory nerve transmitter glutamate. Anti-seizure drugs also inhibit the initiation and propagation of painful nerve impulses by inhibiting Nitric Oxide Synthetase activity [128] [73]. Nitric Oxide Synthetase is the enzyme responsible for the production of the inflammatory mediator Nitric Oxide. Anti-seizure drugs may also protect nerve cells from free radical damage by Nitric Oxide and/or hydroxyl radicals (OH*) [129] [74] . In one study, the anti-seizure drug Sodium valproate was shown to significantly inhibit immune cell production of TNF-alpha and Interleuken-6 [130] [75]. Sodium valproate suppresses TNF-alpha and IL-6 production via inhibition of activation of the nuclear transcription factor kappa B (NF-kappaB). In immune cells and human nerve cells, NF-kappaB is essential to the expression of inflammatory cytokines. In addition anti- seizure medications reduce painful muscle spasm. Spasticity from different causes is associated with a deficiency of inhibitory nerve transmitters like gamma aminobutyric acid or an excess of excitatory nerve transmitters such as glutamate. Anti-seizure drugs enhance the inhibition of nerve-muscle activity by gamma aminobutyric acid in the spinal cord [131][76].

THALIDOMIDE AND THALIDOMIDE ANALOGUES

Thalidomide and analogues mainly inhibit tumor necrosis factor alpha (TNF-alpha) synthesis but the drugs also have effects on other cytokines. Thalidomides increase the production of the anti-inflammatory cytokine interleukin-10 (IL-10) in lesioned sciatic nerves. In addition, Thalidomides stimulate the release of the pain relieving natural opioid peptide methionine-enkephalin in the dorsal horn of the spinal cord [132] .

In a recent case report, a 43-year-old woman had injured her hand and developed a severe case of RSD/CRPS that confined her to bed or a wheelchair most of the time. Three years after developing RSD/CRPS, the woman was diagnosed with multiple myeloma. She was started on thalidomide, which has shown promise for treating multiple myeloma. The change in the woman’s condition was “astounding,” as reported by the authors. Within a month, the woman experienced an unexpected improvement in RSD/CRPS symptoms, which nearly disappeared [133]

NERVE BLOCKADE

The role of neural or nerve blocks with local anesthetics with or without anti-inflammatory agents in the treatment and relief of persistent pain is well defined. A nerve fiber is a long cylinder surrounded by a semi permeable (allows only some substances to pass) membrane. This membrane is made up of proteins and lipids (fats). Some of the proteins act as channels, or pores, for the passage of sodium and potassium ions through the membrane.

The conduction of nerve impulses along a nerve fiber is associated with a change in the permeability of the membrane. The channels widen, and sodium ions (Na+) move to the inside of the fiber. At the same time, potassium ions (K+) diffuse out through other channels. As these electrolytes change positions, an electrical charge is set up and the impulses will travel down the nerve fiber. This process is called depolarization. Once the nerve impulse has passed, the channels become smaller. Sodium ions (Na+) are now “pumped” out of the fiber and potassium ions (K+) are pumped back in. The nerve membrane is now repolarized and ready to conduct another impulse.

Local anesthetic agents stabilize nerve membrane by inhibiting the sodium influx required for the initiation and conduction of impulses. The local anesthetic effect of numbness lasts as long as the agent maintains a certain critical concentration in the nerve membrane.

Subsequent to tissue injury, the expression of sodium channels in nerve fibers is altered significantly thus leading to abnormal excitability in the sensory neurons. Studies have shown that the inflammatory mediators interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist and inducible nitric oxide synthetase are significantly increased when there is excessive nerve traffic as occurs during seizures or persistent pain [134][72]. Local anesthetic agents like anti-epileptic medications decrease pain by reducing the rate of continuing discharge of injured and inflamed nerve fibers. Blockade of sodium channels in nerve cells leads to a decrease in electrical activity and a subsequent reduction in release of the excitatory nerve transmitter glutamate.

Researchers have found that preemptive analgesia — delivering pain medication to patients before or just after surgery — results in significant pain reduction long afterward – for a period that significantly exceeds the duration of action of the local anesthetic or analgesic medication. Beginning pain treatment before or immediately after surgery can vastly decrease post-operative pain [135] [136] [137] .

SURGERY

The role of surgery is uncontested when there is an underlying surgical condition such as a fracture or perforated appendix that produces a continuous aggravation and ongoing production of inflammatory mediators that cannot be controlled by medical intervention. Surgery should not be performed just to treat a structural abnormality and will often be counter productive if a persistent pain condition is amenable to biochemical intervention as described in this book.