Double Blind Placebo Controlled Study of Outpatient Intravenous Ketamine for the Treatment of CRPS
Condition: Complex Regional Pain Syndrome
MeSH terms: Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy
Study type: Interventional
Phase: Phase 2

Summary: 
      Complex Regional Pain Syndrome is a debilitating and extremely difficult to treat condition.
      There is a large body of evidence demonstrating the therapeutic value of N-methyl-D-aspartate
      (NMDA)-receptor antagonists in CRPS. The NMDA antagonist ketamine has been shown to be
      effective in the treatment of CRPS, resulting in complete remission of the disease in some
      patients. The purpose of this study is to evaluate intravenous outpatient infusion of
      sub-anesthetic doses of ketamine for the treatment of CRPS. A thorough evaluation of this
      procedure, providing information into the degree of relief and which of the constellation of
      RSD symptoms are best alleviated by this procedure would result in the optimization of this
      therapy for the treatment of CRPS.
    

Detailed description: 
      PRE TREATMENT:

      Prior to treatment, after informed consent is obtained, each subject will be randomized into
      the ketamine or placebo (normal saline) infusion group. Both the patient and all other
      individuals involved in the study will be blinded as to the treatment except Guillermo
      Alexander PhD who will be responsible for the randomization and Margaret Rose RN who will be
      responsible for preparing the infusion solution. The patient will then receive a complete
      neurological examination and will be asked to complete a short form McGill and Quality of
      life questionnaires (Attachment 1).

      Two weeks before treatment, 2 week and 3 months post treatment the following sensory and
      motor tests will be performed.

      Thermal Detection Thresholds: Cool detection thresholds, which are mediated via A fibers and
      warm detection thresholds, which are mediated by small unmyelinated C fibers, will be
      determined using the TSA-II NeuroSensory Analyzer (Medoc Advanced Medical Systems U.S.,
      Minneapolis, MN). The device consists of a computer controlled thermoelectric probe with a
      surface area of 9 cm2 that is attached using a velcro strap to the area of skin to be tested
      (thenar eminence and hypothenar eminence in the hands and the dorsal foot). For each trial
      the thermal stimulator starts at the thermo-neutral baseline temperature of 32oC, and
      increases for warming thresholds, or decreases for cooling thresholds, linearly at a rate of
      1oC per second, until the subject pushes a button that stops and records the temperature and
      returns the unit to baseline temperature. Three trials are averaged for cool and for warm
      threshold for each site tested.

      Thermal Pain: Thermal pain tolerance will be determined at the same sites and using the same
      method described above for thermal detection thresholds. The only difference is that for
      thermal pain trials, the subject will be instructed to push the control button (which
      immediately resets the stimulator back to baseline temperature) when the thermal stimulus
      (cold or hot) becomes painful. The TSA-II hardware automatically resets if the temperature
      reaches -10oC (for cooling) or 50oC (for heating) and the control button has not been pushed.
      This temperature range has been determined to not cause damage to skin or underlying tissue.

      Dynamic Mechano-allodynia: Dynamic mechano-allodynia will be determined by stroking the skin
      three times within 5 seconds at a rate of 5 cm/sec with a 2.5 cm wide standard foam
      paintbrush. Allodynia severity will be measured on the subject's response using a numerical
      rating scale. The subject reports both the amount of pain on a 0-10 scale (0: no pain; 10:
      worst pain ever experienced) and the extent to which the sensation spread.

      Static Mechano-allodynia and Temporal Summation: Static mechano-allodynia and temporal
      summation will be determined by pin-prick with a standard safety pin once every three seconds
      for a total of 5 times. The subject will be instructed to report the level of pain on a 0-10
      scale (0: no pain; 10: worst pain ever experienced) and the extent to which the sensation
      spread after each repetition. The test will stop if the subject reports unacceptable pain at
      any point during the test.

      Deep pressure pain thresholds: Deep pressure pain thresholds will be determined with a
      pressure algometer (Wagner Instruments, Greenwich, CT) which is a hand held device with a
      1cm2 rub¬ber tip capable of measuring applied pressures of 0-5 kg. The device is held at a
      90o angle to the body surface being tested. The pressure is gradually increased by 1
      kg/second until the subject reports that the stimulus is painful or a pressure of 4 kg/cm2
      has been reached. In the upper extremity thresholds to pain will be determined at: 1)second
      costosternal joint; 2) acromioclavicular joint; 3) lateral epicondyle; 4) radial styloid; 5)
      ulnar styloid; 6) second metacarpal; 6) fifth metacarpal. In the lower extremity thresholds
      to pain will be determined at: 1) greater trochanter; 2) lateral femoral condyle; 3) tibial
      tubercle; 4) mid shin; 5) medial malleolus; 6) lateral malleolus; 7) first metatarsal; 8)
      fifth metatarsal.

      Quantification of Motor Function (finger tap): Finger tap rate will be determined using a
      computer program developed by our group. The subject is instructed to press the spacebar of a
      standard computer keyboard as fast as possible with the index finger of each hand
      respectively for 30 seconds. The program determines the rate and plots the results.

      Cutaneous Temperature: Skin temperature will be measured by use of an infra-red thermometer
      (Dermatemp Infrared Temperature Scanner, model DT-1001, Exergen Corp., Watertown, MA)

      A pregnancy test will be administered to all females of child bearing potential and blood
      will also be drawn for SMA-20, CBC w/ Differential and a full thyroid panel. All subjects
      will be asked to wear an activity watch until the treatment begins (two week). This watch
      (Attachment 2) will evaluate the subject's level of activity and at random programmed
      intervals records the subject's pain level for the two weeks prior to treatment. This is
      accomplished by sounding a tone at which time the subject is instructed to presses a key pad
      and enter a number from 0-10 (0 = no pain and 10 = unbearable pain). The patient will be
      asked to complete the short form McGill and Quality of life questionnaires weekly until the
      start of the infusions.

      PRE INFUSION:

      On the first day of treatment but prior to the start of the infusions, the patient will be
      weighed, undergo a neurologic exam, have vital signs evaluated and have an intravenous line
      inserted.

      On all ten treatment days, patients on both the ketamine and placebo groups are placed on the
      cardiac monitor for cardiac rhythm, blood pressure, pulse and oxygen saturation monitoring.
      In addition, Clonidine (0.1 mg, po) and Versed (4 mg, iv) will be administered. Clonidine has
      been shown, in animals, to potentiate the neuropathic pain-relieving action of NMDA receptor
      blockers like ketamine while preventing their neurotoxic side effects. Versed at this dose,
      provides mild sedation and relieves anxiety.

      INFUSION PLAN:

      All patients will be infused intravenously with 100 ml of normal saline with or without
      ketamine for four hours (25 ml/hr) daily for 10 days. The maximum intravenous ketamine
      infusion dose for this study will be 0.35 mg/kg/hr, not to exceed 25 mg/hr (100 mg of
      ketamine over a 4 hour period). On the first day, the intravenous ketamine infusion will be
      set to 50% of the maximum rate. On the second day, the intravenous ketamine infusion will be
      increased to 75% of the maximum rate. On the third day, the intravenous ketamine infusion
      will be increased to the maximum rate. The daily ketamine infusion rate is maintained at this
      level for the duration of the ten day study.

      CONSIDERATIONS: (Other Treatments and Meds)

      Increased salivation:

      Glycopyrrolate (Robinul) Initially 1mg TID then maintenance dose BID prn

      Psychiatric symptoms:

      Ativan 1mg - HAVE AVAILABLE prn Continued use of current medications with the exception of
      NMDA receptor blockers such as amantadine, memantine, Magnesium sulfate.

      Administer other adjuncts prn O2 2-3 L/min. via Nasal Cannula - HAVE AVAILABLE prn

      LABS:

      Ketamine Level (red top tube) on infusion days 1, 5, 6 and 10.

      NURSING CARE & ORDERS:

      During the IV Ketamine Infusion:

      Continuous cardiac monitoring, Pulse oximetry with q 1 hr blood pressure monitoring V/S q 1
      hr Versed (2 mg iv) administration may be repeated two hours into or at the completion of the
      infusion.

      Activity:

      Patient can leave infusion chair with assistance for bathroom visit. Patient is allowed to
      bring head set (music) or a book to read. No cell phones or laptop computers are allowed.

      Following the last (10th) infusion, the patient will be seen at two weeks then monthly at the
      Neurology Pain Clinic for the following 3 months. All subjects will be asked to wear an
      activity watch from the time of the last infusion until the two week post treatment visit.
      Patients will be instructed to complete the
    

Intervention name(s): Ketamine; IV NSS; Normal Saline
Intervention type(s): Drug; Other; Other
Intervention description(s): IV Ketamine .35mg/kg times ten days.; Placebo inactive ingredients; INFUSION PLAN:
All patients will be infused intravenously with 100 ml of normal saline for four hours (25 ml/hr) daily for 10 days.Both patient arms will receive 2mg of Versed x two doses IV. They will also receive Clonidine (0.1 mg, po)
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment