Pain Therapeutics - Drugs, Markets and Companies |
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0. Executive Summary 15 1. Basic Aspects of Pain..... 17 Introduction 17 Historical aspects of pain .... 17 Pain definitions ... 19 A glossary of terms relevant to pain ... 20 Pain classification and description ...... 20 Neuropathic pain21 Cancer pain22 Bone pain in cancer .......24 Complex regional pain syndrome .........25 Mechanisms of pain............. 25 Pain pathways ...26 Role of nociceptors in pain transmission ..27 Gate control and neuromatrix theories of pain ..............27 Pain mediators...29 Role of the sympathetic nervous system in pain............29 Visceral pain......29 Pathomechanism of visceral pain.....29 Pathomechanism of neuropathic pain....30 Role of intact nerve fibers in neuropathic pain..........30 Role of cytokines...........30 Role of chemokines .......31 Glial activation and neuropathic pain ......31 Role of CNS innate immunity ..........31 Genetic basis of neuropathic pain ....31 Gene expression changes in neuropathic pain ..........32 Role of free radicals in generation of neuropathic pain ..............32 Chemotherapy-induced neuropathic pain.33 Regulation of pain sensitivity by tetrahydrobiopterin.33 Pathomechanism of migraine...............33 Role of the immune system in pain.......34 Pain and itch .....34 Pathomechanism of itch .35 Clinical aspects of itch....35 Molecular pathophysiology of pain........35 Role of ion channels in pain .36 Role of sodium channels in pain ......36 Role of potassium ion channels .......37 Role of calcium channels in pain......37 Acid-sensing ion channels ..............38 P2X3 ion channels .........39 Role of TRP ion channels in pain......39 Genetic basis of pain ..........40 Study of genes in pain ...40 Pain in the brain.41 Change from acute to chronic pain .......41 Role of neuronal plasticity in pain ....42 Descending facilitatory modulation of pain...............42 Pain and transcriptional repressor DREAM ...............42 Neurochemistry of pain.......43 Molecular elements of pain in the peripheral nervous system.....43 Molecular elements of pain in the central nervous system .........44 Opioid receptors............44 Role of AMPA receptors in chronic pain....44 Kinins ...45 Serotonin .....45 Substance P .45 Excitatory amino acids ...45 Role of nitric oxide in pain ..............46 Prostaglandins ..............46 Endocannabinoids .........48 Protein kinase C ............48 Adenosine and adenosine receptors.49 Vitamin D and pain........49 Vanilloid receptor ..........49 TRPA1 and TRPV1 receptors ..............49 - 4 - Endothelin-B receptors...51 Nerve growth factor and pain..........51 Adrenomedullin as a pain-related peptide51 Biomarkers of pain .............51 Biomarkers of visceral pain.............52 2. Assessment of Pain and Analgesics ............... 53 Introduction 53 Animal models of pain......... 53 An overview ......53 Selection of animal species as models for pain..............53 Types of noxious stimuli......53 Animal models of neuropathic pain.......54 Animal models of arthritis ...54 Animal models of peripheral neuropathy ......55 Limitations of current pain models........55 Biogenic Animal Model of Chronic Pain ..56 Ethical issues concerning animal pain models ...............56 Medical evaluation of pain .. 57 Chronic pain as a manifestation of various diseases.......57 Assessment of pain patients ............... 57 Medical examination ...........57 Measurement of pain ..........58 Quantitative sensory testing 59 Pain measurement tools for neonates and children ........60 Quantitative sensory testing 60 Psychological assessment of pain .........61 Brain imaging in pain..........61 Patient outcomes and quality of life during treatment for chronic pain ....62 Evaluation of analgesics...... 63 Study of pain in humans .....63 Testing of analgesics in humans...........63 Design of clinical trials for pain ............64 Assessment of neuropathic pain...........65 Placebo effect in pain..........65 Role of electronic pain recording in determination of the placebo effect...66 Outcome measures for chronic pain trials.....66 Pain, pain therapies and cognitive function ...67 3. Pharmacotherapy of Pain............... 69 Introduction 69 Mechanism of action of currently used pain medications ........... 69 Non-steroidal antiinflammatory drugs 70 COX-2 inhibitors 70 Celecoxib .....71 Nimesulide ...72 Rofecoxib .....72 Valdecoxib....73 Lumiracoxib..73 Side effects of COX inhibitors..........73 Safety aspects of COX-2 inhibitors in development ...75 Acetaminophen..76 Antioxidants as analgesics.. 76 Opiates and opioids............. 76 Innovations in opioid therapy...............77 Oral transmucosal fentanyl.............77 Use of opioids for chronic non-cancer pain...............78 Opioid receptor modulation for visceral pain .78 Opiorphin..78 N-methyl-D-aspartate receptor antagonists............... 79 Ketamine ...79 CNS 5161...79 Triptans for treatment of non-migrainous pain .......... 79 Capsaicin..... 80 NGX-4010 ..80 Local anesthetics 81 Topical application..............81 Nerve blocks......81 Injection of local anesthetics for analgesia....81 Topical salicylates for the treatment of pain .............. 81 Adjunctive analgesics ......... 82 - 5 - Antidepressants .82 Mechanism of analgesic action of antidepressants ....83 Antiepileptic drugs..............83 Mechanism of action of antiepileptic drugs in neuropathic pain...84 Carbamazepine.............85 Gabapentin...85 Lamotrigine ..86 Phenytoin.....86 Pregabalin ....86 Topiramate...87 Valproic acid.87 Other antiepileptic drugs 88 Clonidine..... 88 Baclofen...... 88 Corticosteroids... 89 Calcitonin.... 89 Bisphosphonates. 89 Botulinum toxins. 90 Analgesic effect of botulinum toxin A ....90 Engineered botulinum toxin.90 Adverse effects of analgesics .............. 91 Gastrointestinal adverse effects of NSAIDs ...91 Measures to reduce gastrointestinal adverse effects of NSAIDs ..91 Cardiovascular adverse effects of COX-2 inhibitors ........91 Adverse effects of opioids....92 Risk of addiction and development of tolerance........92 Hyperalgesia associated with opioids ......93 Respiratory depression ..93 Opioid-associated constipation ........93 Approaches to reduce adverse effects of opioids ...........93 PEGylated naloxol .........94 Remoxy versus Oxycontin ..............94 Innovative approaches to modify opioid pharmacology..............94 Adverse effects of non-narcotic analgesics....94 4. Management of Pain ...... 95 Introduction 95 Sites for pain management . 95 Self-medication at home .....95 Physicians' offices ..............95 Major hospitals ..95 Pain centers ......96 Non-pharmacological approaches to pain .. 96 Alternative medicine...........96 Acupuncture .97 Herbs and other plants ..97 Aromatherapy...............98 Self-Controlled Energo Neuro Adaptive Regulation....98 Behavioral therapy .............99 Cognition and pain ........99 Control over brain activation and pain by using functional MRI...99 Virtual reality therapy ....99 Local application of heat.... 100 Transcutaneous nerve stimulation ...... 100 Transcranial magnetic stimulation ...... 100 Neurosurgery for pain relief............... 101 Ablative procedures on the nervous system........... 101 Procedures on peripheral, spinal and cranial nerves 101 Vagal nerve stimulation for control of pain ............ 102 Neuromodulation......... 102 Spinal cord stimulation 102 Brain stimulation......... 103 Implantation of drug delivery devices ... 103 Management of special types of pain 103 Acute pain 103 Management of acute renal colic: NSAIDS vs. opioids ............. 104 Combination of opioids and NSAIDs...... 104 Reasons for inadequate management of acute pain 104 Perioperative pain management......... 104 Opioids for perioperative pain ....... 105 Ketamine for perioperative pain .... 105 - 6 - Drug combination for perioperative pain 106 Perioperative pain in neurosurgery 106 Devices for delivery of analgesics in the postoperative period .. 106 Pain associated with sports and exercise .... 107 Chronic abdominal pain..... 107 Functional somatic syndromes ........... 108 Fibromyalgia syndrome..... 108 Pathomechanism of FMS .............. 109 Management of FMS .... 109 New developments in pharmacotherapy of FMS ..... 109 Erythromelalgia ............... 110 Irritable bowel syndrome .. 110 Opioids for IBS ........... 111 Tricyclic antidepressants for IBS.... 112 Serotonin-modulating drugs for IBS...... 112 Musculoskeletal pain......... 112 Myofascial pain syndrome . 112 Osteoarthritis .. 113 Rheumatoid arthritis......... 115 Management of pain in rheumatoid arthritis........... 115 Disease modifying therapies in rheumatoid arthritis 115 Resurgence of interest in gold-based treatments for RA .......... 116 Backache . 117 Use of analgesics for management of back pain ..... 118 Miscellaneous medical therapies for backache and sciatica ...... 119 Neck pain. 119 Chronic pelvic pain ........... 119 Prostatitis... 120 Cancer pain..... 120 Opioid treatment of cancer pain .... 121 Breakthrough and opioid-insensitive pains............. 122 Methods of delivery of opioids for cancer pain........ 122 Implantation of drug delivery devices ... 123 Management of bone pain in cancer...... 123 Use of non-opioid analgesics for cancer pain.......... 124 Adjuvant drugs for cancer pain ..... 124 Radiation therapy........ 124 Alternative non-pharmacological methods ............. 124 Anesthetic techniques.. 124 Surgical methods of cancer pain relief... 125 Conclusions regarding management of cancer pain. 125 Chronic non-malignant pain............... 125 Headache. 126 Migraine..... 126 Management of acute migraine ..... 127 Neurostimulation for migraine....... 130 Transcranial magnetic stimulation for migraine ...... 131 Cluster headache ........ 131 Tension headache ....... 132 Chronic daily headache 132 Trigeminal neuralgia......... 133 Dental pain...... 134 Neuropathic pain.............. 134 Management of central neuropathic pain............... 135 Pharmacotherapy of central neuropathic pain ........ 136 Chronobiology of neuropathic pain as guide to therapy ........... 137 Neurosurgical approaches to central neuropathic pain............. 138 Syringomyelia............. 138 Neuropathic pain associated with spinal cord injury 139 Peripheral neuropathic pain .......... 139 Management of chemotherapy-induced pain .......... 139 Morton’s neuroma ....... 140 Management of diabetic neuropathy ..... 140 Postherpetic neuralgia . 142 Complex regional pain syndrome... 143 Evidence-based management of neuropathic pain .. 145 An algorithm for the management of peripheral neuropathic pain.... 145 Phantom limb pain ........... 146 Pathomechanism of phantom limb pain . 146 Management of phantom limb pain 147 Pain and depression ......... 148 - 7 - Neurochemical link between pain and depression ... 149 Management of chronic pain and depression.......... 150 Miscellaneous painful conditions......... 150 Pain in Parkinson's disease ........... 150 Burning mouth syndrome ............. 151 Ophthalmic pain.......... 151 Chronic unstable angina............... 151 Management of itching...... 152 Topical applications for itching ...... 152 Systemic therapies for itching....... 153 Non-pharmacological therapies for itch . 154 Management of pain in special population groups ... 154 Racial and ethnic differences in pain management....... 154 Pain in neonates .............. 154 Management of pain in children ......... 155 Management of pain in the elderly...... 156 Management of pain in the cognitively impaired elderly people ..... 157 Management of pain in women .......... 157 Reasons for increased pain perception in women.... 158 Chronic pelvic pain in women........ 158 Gender differences in response to analgesics ......... 158 Considerations for pain management in women ..... 159 Management of pain in neurologically handicapped persons.......... 159 Management of pain in the terminally ill..... 159 Deficiencies in the management of pain... 160 Negative physician attitudes in pain management ....... 160 Suggestions for improvement of pain management by healthcare providers .......... 161 Pain as the fifth vital sign .. 162 Multidisciplinary approaches to pain management .. 162 Pharmacoeconomic aspects of pain management .... 163 5. Drug Delivery for Pain . 165 Introduction..... 165 Intra-articular injection for relief of joint pain......... 166 Controlled release drug delivery for pain . 166 Accelerating the effect of subcutaneous morphine ....... 166 Controlled drug delivery at site of pain 166 Oral extended release opioids ............ 167 Extended release oral morphine .... 167 Controlled release oxycodone ....... 167 Extended release oxymorphone .... 168 Oral extended release tramadol .... 168 Extended release gabapentin ........ 168 Use of nanotechnology for drug delivery for pain......... 169 Non-injection methods of delivery of analgesics...... 169 Topical applications for pain .............. 170 Topical local anesthetics............... 170 Topical NSAIDs ........... 170 Topical and transdermal diclofenac 171 Topical application for postoperative pain .............. 171 Needle-free drug delivery for pain ...... 172 Transdermal drug delivery for pain..... 172 Relief of pain associated with minor medical procedures.......... 172 Transdermal fentanyl... 172 Transdermal ketoprofen ............... 173 Transdermal nitroglycerine as an adjuvant to opioids.............. 175 Transdermal buprenorphine.......... 175 Powder Injection Systems ............ 175 Intranasal delivery of analgesics ........ 176 Intranasal morphine .... 176 Intranasal diamorphine 176 Intranasal fentanyl ...... 177 Intranasal buprenorphine ............. 177 Intranasal ketamine .... 177 Intranasal ketorolac..... 178 | |