title: Local administration of norepinephrine in the stump evokes dose-dependent pain in amputees.
abstract: BACKGROUND
  More than 50% of amputees report experiencing significant stump or phantom pain. Stump pain is often attributed to the formation of a neuroma at the amputation site. Experimental evidence shows that catecholamines and alpha-adrenoceptors play a role in the mechanisms of pain associated with neuromas. We investigated whether administration of physiological doses of norepinephrine (NE) in the distal stump in the region of a probable neuroma evoked pain and if local administration of phentolamine attenuated NE-evoked pain in patients with postamputation stump pain.
  
  
  METHODS
  Twenty patients with postamputation stump pain participated in the study. In 15 patients, 0.2 mL of saline and NE (10(-7), 10(-6), and 10(-5) molar concentrations) were administered sequentially in a single blinded fashion in the region of maximal tenderness and Tinel sign, a probable site of a neuroma. In 12 of these 15 patients, pain evoked by 0.2 mL of 10(-5) M NE was examined before and after the injection of 0.2 mL phentolamine 10(-4) M. Patients rated their pain using a computer-based visual analog scale. The area under the curve was calculated for pain evoked by each injection and the scores were normalized to the first saline injection.
  
  
  RESULTS
  The perineuronal administration of NE had a dose-dependent increase in pain (P=0.005). In contrast, repeated saline injections did not result in increased evoked pain. There was a partial reversal of the pain evoked by 10(-5) M NE after pretreatment with phentolamine (NE 10(-5) M prephentolamine versus normal saline P=0.02, NE 10(-5) M postphentolamine versus normal saline P=0.054).
  
  
  CONCLUSIONS
  Our data suggest that alpha-adrenoceptor mechanisms contribute to stump pain, possibly associated with neuromas in amputees. Sympathectomy and adrenergic blockade should be explored in controlled clinical trials as therapeutic options in patients with postamputation pain.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Elaina E
authors.initials: EE
authors.lastname: Lin
authors.forename: Sylvia
authors.initials: S
authors.lastname: Horasek
authors.forename: Shefali
authors.initials: S
authors.lastname: Agarwal
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wu
authors.forename: Srinivasa N
authors.initials: SN
authors.lastname: Raja
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D000672:Amputation Stumps; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000008:administration & dosage*; D010149:Postoperative Pain / Q000517:prevention & control*; D010646:Phentolamine / Q000008:administration & dosage; D013566:Sympathomimetics / Q000008:administration & dosage*
chemical_list: D000317:Adrenergic alpha-Antagonists; D013566:Sympathomimetics; D009638:Norepinephrine; D010646:Phentolamine