Low dose ketamine reduces pain perception and blood pressure, but not muscle sympathetic nerve activity, responses during a cold pressor test

Joseph C Watso, Mu Huang, Gilbert Moralez, Matthew N Cramer, Joseph M Hendrix, Frank A Cimino 3rd, Luke N Belval, Carmen Hinojosa-Laborde, Craig G Crandall, Joseph C Watso, Mu Huang, Gilbert Moralez, Matthew N Cramer, Joseph M Hendrix, Frank A Cimino 3rd, Luke N Belval, Carmen Hinojosa-Laborde, Craig G Crandall

Abstract

Key points: Low dose ketamine is a leading medication used to provide analgesia in pre-hospital and hospital settings. Low dose ketamine is increasingly used off-label to treat conditions such as depression. In animals, ketamine stimulates the sympathetic nervous system and increases blood pressure, but these physiological consequences have not been studied in conscious humans. Our data suggest that low dose ketamine administration blunts pain perception and reduces blood pressure, but not muscle sympathetic nerve activity burst frequency, responses during a cold pressor test in healthy humans. These mechanistic, physiological results inform risk-benefit analysis for clinicians administering low dose ketamine in humans.

Abstract: Low dose ketamine is an effective analgesic medication. However, our knowledge of the effects of ketamine on autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low dose ketamine influences autonomic cardiovascular responses during painful stimuli in humans. We tested the hypothesis that low dose ketamine blunts perceived pain, and blunts subsequent sympathetic and cardiovascular responses during an experimental noxious stimulus. Twenty-two adults (10F/12M; 27 ± 6 years; 26 ± 3 kg m-2 , mean ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed cold pressor tests (CPT; hand in ∼0.4°C ice bath for 2 min) pre- and 5 min post-drug administration (20 mg ketamine or saline). We compared pain perception (100 mm visual analogue scale), muscle sympathetic nerve activity (MSNA; microneurography, 12 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) during the pre- and post-drug CPTs separately using paired, two-tailed t tests. For the pre-drug CPT, perceived pain (P = 0.4378), MSNA burst frequency responses (P = 0.7375), and mean BP responses (P = 0.6457) were not different between trials. For the post-drug CPT, ketamine compared to placebo administration attenuated perceived pain (P < 0.0001) and mean BP responses (P = 0.0047), but did not attenuate MSNA burst frequency responses (P = 0.3662). Finally, during the post-drug CPT, there was a moderate relation between cardiac output and BP responses after placebo administration (r = 0.53, P = 0.0121), but this relation was effectively absent after ketamine administration (r = -0.12, P = 0.5885). These data suggest that low dose ketamine administration attenuates perceived pain and pressor, but not MSNA burst frequency, responses during a CPT.

Keywords: analgesia; blood pressure; muscle sympathetic nerve activity.

© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.

References

    1. Adlan AM, Paton JF, Lip GY, Kitas GD & Fisher JP (2017). Increased sympathetic nerve activity and reduced cardiac baroreflex sensitivity in rheumatoid arthritis. J Physiol 595, 967-981.
    1. Ahern TL, Herring AA, Miller S & Frazee BW (2015). Low-dose ketamine infusion for emergency department patients with severe pain. Pain Medicine 16, 1402-1409.
    1. Asmundsson G, Mokler DJ & Ally A (1998). Effects of ventrolateral medullary NMDA-receptor antagonism on biogenic amines and pressor response to muscle contraction. Neurosci Res 32, 47-56.
    1. Atashkhoyi S, Negargar S & Hatami-Marandi P (2013). Effects of the addition of low-dose ketamine to propofol-fentanyl anaesthesia during diagnostic gynaecological laparoscopy. Eur J Obstet Gynecol Reprod Biol 170, 247-250.
    1. Azari P, Lindsay DR, Briones D, Clarke C, Buchheit T & Pyati S (2012). Efficacy and safety of ketamine in patients with complex regional pain syndrome: a systematic review. CNS Drugs 26, 215-228.
    1. Banov MD, Young JR, Dunn T & Szabo ST (2019). Efficacy and safety of ketamine in the management of anxiety and anxiety spectrum disorders: a review of the literature. CNS Spectr 25, 331-342.
    1. Basuni AS(2016). Addition of low-dose ketamine to midazolam and low-dose bupivacaine improves hemodynamics and postoperative analgesia during spinal anesthesia for cesarean section. J Anaesthesiol Clin Pharmacol 32, 44.
    1. Bredmose P, Lockey D, Grier G, Watts B & Davies G (2009). Pre-hospital use of ketamine for analgesia and procedural sedation. Emerg Med J 26, 62-64.
    1. Bruehl S, Olsen RB, Tronstad C, Sevre K, Burns JW, Schirmer H, Nielsen CS, Stubhaug A & Rosseland LA (2018). Chronic pain-related changes in cardiovascular regulation and impact on comorbid hypertension in a general population: the Tromsø study. Pain 159, 119-127.
    1. Burgmer M, Petzke F, Giesecke T, Gaubitz M, Heuft G & Pfleiderer B (2011). Cerebral activation and catastrophizing during pain anticipation in patients with fibromyalgia. Psychosom Med 73, 751-759.
    1. Busnardo C, Tavares RF & Corrêa FM (2009). Role of N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors in the cardiovascular effects of L-glutamate microinjection into the hypothalamic paraventricular nucleus of unanesthetized rats. J Neurosci Res 87, 2066-2077.
    1. Butler FK, Kotwal RS, Buckenmaier CC, Edgar EP, O'Connor KC, Montgomery HR, Shackelford SA, Gandy JV, Wedmore IS, Timby JW, Gross KR & Bailey JA (2014). A triple-option analgesia plan for tactical combat casualty care: TCCC guidelines change 13-04. J Spec Oper Med 14, 13-25.
    1. Camargo LH, Alves FH, Biojone C, Correa FM, Resstel LB & Crestani CC (2013). Involvement of N-methyl-d-aspartate glutamate receptor and nitric oxide in cardiovascular responses to dynamic exercise in rats. Eur J Pharmacol 713, 16-24.
    1. Cheuvront SN, Ely BR, Kenefick RW & Sawka MN (2010). Biological variation and diagnostic accuracy of dehydration assessment markers. Am J Clin Nutr 92, 565-573.
    1. Clements JA & Nimmo WS (1981). Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 53, 27-30.
    1. Domany Y, Bleich-Cohen M, Tarrasch R, Meidan R, Litvak-Lazar O, Stoppleman N, Schreiber S, Bloch M, Hendler T & Sharon H (2019). Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry 214, 20-26.
    1. Fagius J, Karhuvaara S & Sundlöf G (1989). The cold pressor test: effects on sympathetic nerve activity in human muscle and skin nerve fascicles. Acta Physiol Scand 137, 325-334.
    1. Fairfax ST, Holwerda SW, Credeur DP, Zuidema MY, Medley JH, Dyke PC, Wray DW, Davis MJ & Fadel PJ (2013). The role of α-adrenergic receptors in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man. J Physiol 591, 3637-3649.
    1. Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, Ionescu DF, Mathew SJ, Chang LC, Iosifescu DV, Murrough J, Debattista C, Schatzberg AF, Trivedi MH, Jha MK, Sanacora G, Wilkinson ST & Papakostas GI (2020). Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 25, 1592-1603.
    1. Fazalbhoy A, Birznieks I & Macefield V (2012). Individual differences in the cardiovascular responses to tonic muscle pain: parallel increases or decreases in muscle sympathetic nerve activity, blood pressure and heart rate. Exp Physiol 97, 1084-1092.
    1. Fazalbhoy A, Birznieks I & Macefield V (2014). Consistent interindividual increases or decreases in muscle sympathetic nerve activity during experimental muscle pain. Exp Brain Res 232, 1309-1315.
    1. Gagnon D, Romero SA, Ngo H, Poh PY & Crandall CG (2017). Plasma hyperosmolality improves tolerance to combined heat stress and central hypovolemia in humans. Am J Physiol Regul Integr Comp Physiol 312, R273-R280.
    1. Galinski M, Dolveck F, Combes X, Limoges V, Smaïl N, Pommier V, Templier F, Catineau J, Lapostolle F & Adnet F (2007). Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med 25, 385-390.
    1. Gausche-Hill M, Brown KM, Oliver ZJ, Sasson C, Dayan PS, Eschmann NM, Weik TS, Lawner BJ, Sahni R & Falck-Ytter Y (2014). An evidence-based guideline for prehospital analgesia in trauma. Prehosp Emerg Care 18, 25-34.
    1. Guelen I, Westerhof BE, Van Der Sar GL, Van Montfrans GA, Kiemeneij F, Wesseling KH & Bos WJ (2003). Finometer, finger pressure measurements with the possibility to reconstruct brachial pressure. Blood Press Monit 8, 27-30.
    1. Hallman DM, Lindberg L-G, Arnetz BB & Lyskov E (2011). Effects of static contraction and cold stimulation on cardiovascular autonomic indices, trapezius blood flow and muscle activity in chronic neck-shoulder pain. Eur J Appl Physiol 111, 1725-1735.
    1. Huang M, Yoo JK, Stickford ASL, Moore JP, Hendrix JM, Crandall CG & Fu Q (2019). Early sympathetic neural responses during a cold pressor test linked to pain perception. Clin Auton Res (in press; ).
    1. Jansen JR, Schreuder JJ, Mulier JP, Smith NT, Settels JJ & Wesseling KH (2001). A comparison of cardiac output derived from the arterial pressure wave against thermodilution in cardiac surgery patients. Br J Anaesth 87, 212-222.
    1. Jennings PA, Cameron P & Bernard S (2011). Ketamine as an analgesic in the pre-hospital setting: a systematic review. Acta Anaesthesiol Scand 55, 638-643.
    1. Joyner MJ, Charkoudian N & Wallin GB (2010). Sympathetic nervous system and blood pressure in humans: individualized patterns of regulation and their implications. Hypertension 56, 10-16.
    1. Karlow N, Schlaepfer CH, Stoll CRT, Doering M, Carpenter CR, Colditz GA, Motov S, Miller J & Schwarz ES (2018). A systematic review and meta-analysis of ketamine as an alternative to opioids for acute pain in the emergency department. Acad Emerg Med 25, 1086-1097.
    1. Kienbaum P, Heuter T, Michel MC & Peters J (2000). Racemic ketamine decreases muscle sympathetic activity but maintains the neural response to hypotensive challenges in humans. Anesthesiology 92, 94-101.
    1. Kregel KC, Seals DR & Callister R (1992). Sympathetic nervous system activity during skin cooling in humans: relationship to stimulus intensity and pain sensation. J Physiol 454, 359-371.
    1. Lacourt TE, Houtveen JH & van Doornen LJP (2012). Experimental pressure-pain assessments: test-retest reliability, convergence and dimensionality. Scand J Pain 3, 31-37.
    1. Lauritsen C, Mazuera S, Lipton RB & Ashina S (2016). Intravenous ketamine for subacute treatment of refractory chronic migraine: a case series. J Headache Pain 17, 106.
    1. Li Z & Chen Y (2019). Ketamine reduces pain and opioid consumption after total knee arthroplasty: a meta-analysis of randomized controlled studies. Int J Surg 70, 70-83.
    1. Liebe T, Li S, Lord A, Colic L, Krause AL, Batra A, Kretzschmar MA, Sweeney-Reed CM, Behnisch G, Schott BH & Walter M (2017). Factors influencing the cardiovascular response to subanesthetic ketamine: a randomized, placebo-controlled trial. Int J Neuropsychopharmacol 20, 909-918.
    1. Losvik OK, Murad MK, Skjerve E & Husum H (2015). Ketamine for prehospital trauma analgesia in a low-resource rural trauma system: a retrospective comparative study of ketamine and opioid analgesia in a ten-year cohort in Iraq. Scand J Trauma Resusc Emerg Med 23, 94.
    1. Lundy PM, Gverzdys S & Frew R (1985). Ketamine: evidence of tissue specific inhibition of neuronal and extraneuronal catecholamine uptake processes. Can J Physiol Pharmacol 63, 298-303.
    1. Macefield V(2020). Recording and quantifying sympathetic outflow to muscle and skin in humans: methods, caveats and challenges. Clin Auton Res (in press; ).
    1. Mayer M, Ochmann O, Doenicke A, Angster R & Suttmann H (1990). The effect of propofol-ketamine anesthesia on hemodynamics and analgesia in comparison with propofol-fentanyl. Anaesthesist 39, 609-616.
    1. Metzler-Wilson K, Vrable A, Schaub A, Schmale TK, Rodimel BV, Krause BA & Wilson TE (2019). Effect of suboccipital release on pain perception and autonomic reflex responses to ischemic and cold pain. Pain Med (in press; ).
    1. Miyawaki I, Nakamura K, Terasako K, Toda H, Kakuyama M & Mori K (1995). Modification of endothelium-dependent relaxation by propofol, ketamine, and midazolam. Anesth Analg 81, 474-479.
    1. Nakamura T, Kawabe K & Sapru HN (2008). Cold pressor test in the rat: medullary and spinal pathways and neurotransmitters. Am J Physiol Heart Circ Physiol 295, H1780-H1787.
    1. Ogawa A, Uemura M, Kataoka Y, Ol K & Inokuchi T (1993). Effects of ketamine on cardiovascular responses mediated by N-methyl-D-aspartate receptor in the rat nucleus tractus solitarius. Anesthesiology 78, 163-167.
    1. Peckerman A, Hurwitz BE, Saab PG, Llabre MM, McCabe PM & Schneiderman N (1994). Stimulus dimensions of the cold pressor test and the associated patterns of cardiovascular response. Psychophysiology 31, 282-290.
    1. Peckerman A, Saab PG, McCabe PM, Skyler JS, Winters RW, Llabre MM & Schneiderman N (1991). Blood pressure reactivity and perception of pain during the forehead cold pressor test. Psychophysiology 28, 485-495.
    1. Petz LN, Tyner S, Barnard E, Ervin A, Mora A, Clifford J, Fowler M & Bebarta VS (2015). Prehospital and en route analgesic use in the combat setting: a prospectively designed, multicenter, observational study. Mil Med 180, 14-18.
    1. Pfenninger E, Baier C, Claus S & Hege G (1994). Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses. Anaesthesist 43, S68-75.
    1. Porter K(2004). Ketamine in prehospital care. Emerg Med J 21, 351-354.
    1. Riva-Posse P, Reiff CM, Edwards JA, Job GP, Galendez GC, Garlow SJ, Saah TC, Dunlop BW & McDonald WM (2018). Blood pressure safety of subanesthetic ketamine for depression: a report on 684 infusions. J Affect Disord 236, 291-297.
    1. Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P & Nemeroff CB (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 74, 399-405.
    1. Schauer SG, Naylor JF, Maddry JK, Hinojosa-Laborde C & April MD (2019). Trends in prehospital analgesia administration by US Forces From 2007 through 2016. Prehosp Emerg Care 23, 271-276.
    1. Schobel HP, Ringkamp M, Behrmann A, Forster C, Schmieder RE & Handwerker HO (1996). Hemodynamic and sympathetic nerve responses to painful stimuli in normotensive and borderline hypertensive subjects. Pain 66, 117-124.
    1. Shackelford SA, Fowler M, Schultz K, Summers A, Galvagno SM, Gross KR, Mabry RL, Bailey JA, Kotwal RS & Butler FK (2015). Prehospital pain medication use by US Forces in Afghanistan. Mil Med 180, 304-309.
    1. Singh H, Kundra S, Singh RM, Grewal A, Kaul TK & Sood D (2013). Preemptive analgesia with ketamine for laparoscopic cholecystectomy. J Anaesthesiol Clin Pharmacol 29, 478.
    1. Slogoff S & Allen GW (1974). The role of baroreceptors in the cardiovascular response to ketamine. Anesth Analg 53, 704-707.
    1. Stancak A, Yamamotova A, Kulis P & Sekyra V (1996). Cardiovascular adjustments and pain during repeated cold pressor test. Clin Auton Res 6, 83-89.
    1. Traber DL & Wilson RD (1969). Involvement of the sympathetic nervous system in the pressor response to ketamine. Anesth Analg 48, 248-252.
    1. Victor RG, Leimbach WN Jr, Seals DR, Wallin BG & Mark AL (1987). Effects of the cold pressor test on muscle sympathetic nerve activity in humans. Hypertension 9, 429-436.
    1. Volkow ND & Collins FS (2017). The role of science in addressing the opioid crisis. N Engl J Med 377, 391-394.
    1. Wallin BG & Nerhed C (1982). Relationship between spontaneous variations of muscle sympathetic activity and succeeding changes of blood pressure in man. J Auton Nerv Syst 6, 293-302.
    1. Wang WZ, Rong WF, Wang JJ & Yuan WJ (2001). Effect of ketamine on presympathetic neurons in rostral ventrolateral medulla of rats. Acta Pharmacol Sin 22, 97-102.
    1. Watso JC, Babcock MC, Robinson AT, Migdal KU, Wenner MM, Stocker SD & Farquhar WB (2019). Water deprivation does not augment sympathetic or pressor responses to sciatic afferent nerve stimulation in rats or to static exercise in humans. J Appl Physiol 127, 235-245.
    1. Watso JC, Robinson AT, Babcock MC, Migdal KU, Wenner MM, Stocker SD & Farquhar WB (2020). Short-term water deprivation does not increase blood pressure variability or impair neurovascular function in healthy young adults. Am J Physiol Regul Integr Comp Physiol 318, R112-R121.
    1. Wesseling KH, Jansen JR, Settels JJ & Schreuder JJ (1993). Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 74, 2566-2573.
    1. White DW, Shoemaker JK & Raven PB (2015). Methods and considerations for the analysis and standardization of assessing muscle sympathetic nerve activity in humans. Auton Neurosci 193, 12-21.
    1. Zaidi R & Ahmed A (2015). Comparison of ketorolac and low-dose ketamine in preventing tourniquet-induced increase in arterial pressure. Indian J Anaesth 59, 428.
    1. Zamunér AR, Barbic F, Dipaola F, Bulgheroni M, Diana A, Atzeni F, Marchi A, Sarzi-Puttini P, Porta A & Furlan R (2015). Relationship between sympathetic activity and pain intensity in fibromyalgia. Clin Exp Rheumatol 33, S53-57.

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