1521-0081/12/6403-722–779$25.00 PHARMACOLOGICAL REVIEWS Vol. 64, No. 3 Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 5447/3781330 Pharmacol Rev 64:722–779, 2012 ASSOCIATE EDITOR: ULF SIMONSEN Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs Anne Estrup Olesen, Trine Andresen, Camilla Staahl, and Asbjørn Mohr Drewes Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark (A.E.O., T.A., A.M.D.); Gru¨nenthal GmBH,R&D,Aachen, Germany (C.S.); and Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark (A.M.D.) Abstract............................................................................... 724 Downloaded from I. Introduction ........................................................................... 725 II. The pain system ....................................................................... 725 A. Macro anatomy and mechanisms ..................................................... 725 1. Sensory nerves .................................................................. 725 a. Nociceptors in skin ............................................................ 725 b. Nociceptors in muscle and bone................................................. 726 pharmrev.aspetjournals.org c. Nociceptors in viscera ......................................................... 726 2. The spinal level.................................................................. 727 3. The supraspinal level ............................................................ 727 4. The sensitized pain system ....................................................... 729 B. Cellular and receptor level........................................................... 729 1. Pain physiology .................................................................. 729 2. Plasticity and sensitization ....................................................... 730 III. Animal versus human pain models ...................................................... 732 at Univ of Pittsburgh, HSLS on September 9, 2013 IV. Clinical studies versus experimental human pain models .................................. 733 V. Experimental human pain models ....................................................... 734 A. Skin ............................................................................... 734 1. Mechanical stimulation........................................................... 734 a. Touch ........................................................................ 735 b. Pinprick...................................................................... 735 c. Pressure ..................................................................... 735 2. Electrical stimulation ............................................................ 735 3. Thermal stimulation.............................................................. 735 a. Cold ......................................................................... 735 b. Contact heat.................................................................. 735 c. Laser ........................................................................ 736 4. Models evoking hyperalgesia ...................................................... 736 a. Capsaicin .................................................................... 736 b. Nerve growth factor ........................................................... 737 c. Glutamate.................................................................... 737 d. Burn injury................................................................... 737 e. Freeze lesion ................................................................. 737 f. Mustard oil................................................................... 737 g. Menthol ...................................................................... 738 h. Acid phosphate buffer ......................................................... 738 i. Sodium lauryl sulfate.......................................................... 738 j. Pinch ........................................................................ 738 k. Electrical stimulation.......................................................... 738 B. Muscle and bone.................................................................... 738 Address correspondence to: Dr. Anne Estrup Olesen, Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark. E-mail: [email protected] This article is available online at http://pharmrev.aspetjournals.org. http://dx.doi.org/10.1124/pr.111.005447. 722 PHARMACOLOGY OF HUMAN PAIN MODELS 723 1. Mechanical stimulation. .......................................................... 739 a. Muscle ....................................................................... 739 b. Bone ......................................................................... 739 2. Electrical stimulation ............................................................ 739 3. Thermal stimulation ............................................................. 739 4. Models evoking hyperalgesia. ..................................................... 740 a. Ischemic stimulation .......................................................... 740 b. Exercise-induced muscle pain .................................................. 740 c. Chemically induced muscle hyperalgesia ........................................ 740 C. Viscera ............................................................................ 741 1. Mechanical stimulation........................................................... 741 2. Electrical stimulation ............................................................ 742 3. Thermal stimulation ............................................................. 742 4. Models evoking hyperalgesia ...................................................... 742 VI. Experimental pain modulation .......................................................... 743 A. Conditioned pain modulation ........................................................ 743 B. Summation ........................................................................ 743 C. Thermal stimulation ................................................................ 743 D. Chemical stimulation ............................................................... 743 E. Long-term potentiation/depression.................................................... 744 VII. Pain assessment ....................................................................... 744 A. Psychophysical methods ............................................................. 744 1. One-dimensional pain assessment tools ............................................ 744 2. Multidimensional pain assessment tools............................................ 744 B. Neurophysiological methods ......................................................... 745 1. Magnetic resonance imaging ...................................................... 745 2. Single photon emission computed tomography and positron emission tomography ...... 745 3. Electroencephalography .......................................................... 745 4. Magnetoencephalography ......................................................... 746 C. The nociceptive withdrawal reflex .................................................... 746 D. Referred pain area .................................................................. 746 VIII. Analgesic assessment by experimental human pain models in healthy volunteers ............ 747 A. Nonopioids ......................................................................... 747 1. Nonsteroidal anti-inflammatory drugs and acetaminophen ........................... 747 a. Acetylsalicylic acid (aspirin) .................................................... 747 b. Ibuprofen .................................................................... 747 c. Ketorolac. .................................................................... 748 d. Acetaminophen (paracetamol)................................................... 748 2. N-Methyl-D-aspartate antagonists.................................................. 749 a. Ketamine .................................................................... 749 3. Adjuvant analgesics. ............................................................. 750 a. Gabapentin and pregabalin .................................................... 750 b. Lamotrigine .................................................................. 750 c. Imipramine................................................................... 751 B. Opioids ............................................................................ 751 1. Short-acting opioids .............................................................. 751 a. Alfentanil and remifentanil .................................................... 751 2. Longer acting opioids. ............................................................ 752 a. Traditional ␮-receptor agonists ................................................. 752 b. Opioids with weak affinity for the ␮-opioid receptor .............................. 755 c. ␬-Receptor agonists............................................................ 756 3. Opioids with mixed binding profile. ................................................ 756 a. Tramadol. .................................................................... 756 C. Other types of analgesics ............................................................ 756 1. Cannabinoids...................................................................