The overall goal of this methodology is to evaluate analgesics and provide information on a drug's pharmacology, and allow them to be fully characterized and profiled. These pain tasks can help answer key questions in the pain research field, such as whether a new potential analgesic is effective in reducing a certain type of pain. The main advantage of this technique is that the tasks are able to profile a wide range of analgesics and have been shown predictive validity and reproducibility.
Generally, individuals new to this method will struggle, as pain tasks need to be administered in a consistent manner, and equipment setup is complex and needs custom operating scripts. Prior to the assessment tasks, obtain informed consent. Then provide instructions for pain scoring.
Introduce the subject to the electronic Visual Analogue Scale slider, and instruct them to indicate the intensity of their pain on a scale from zero to 100%or intolerable pain, by moving the slider from left to right. Inform them that moving the slider all the way to the right ends the administration of the painful stimulus. Provide standardized definitions and instructions for pain scale reporting during training, and whenever necessary throughout the experiments.
Next, prepare the area 100 millimeters distal from the caudal end of the patella for the electrical stimulation task. Shave the skin if necessary. Then clean the area overlying the tibia bone using skin preparation gel.
Then place two silver-silver chloride electrodes on the prepared skin. The middle of the anode should be placed 100 millimeters distal to the caudal end of the patella, and the middle of the cathode should be directly underneath the first. Next, instruct the subject to sit comfortably with their foot flat on the floor and record the resistance of the two electrodes to ensure that it is less than two kiloohms.
If necessary, remove the electrodes and re-cleanse the skin with skin preparation gel. Connect the electrodes to a constant current stimulator and apply a tetanic pulse from zero milliamps in steps of 0.5 milliamps per second, with a frequency of ten Hertz and a duration of 0.2 milliseconds. Use the Visual Analogue Scale and record when stimulus becomes painful, corresponding to a pain detection threshold rating over zero.
Also record when the pain level is no longer tolerable to the subject, then end administration of the painful stimulus and record the area under the stimulus response curve. For the pressure stimulation task, first place an 11 centimeter wide tourniquet cuff over the subject's gastrocnemius muscle. Then instruct the subject to sit comfortably with their feet flat on the floor during testing.
Now inflate the cuff with a constant pressure rate increase of 0.5 kilopascals per second up to 100 kilopascals, controlling the pressure with an electro-pneumatic regulator. As before, the subject should rate their pain response as the cuff is inflated using the electronic Visual Analogue Scale. The stimulus should be ceased by deflating the cuff if the subject indicates intolerable pain or the cuff reaches a pressure of 100 kilopascals.
For the cold pressor task, begin by preparing two thermostat-controlled circulating water baths set at 35 degrees Celsius and one degree Celsius. Immediately prior to commencing the test, measure the subject's resting diastolic blood pressure. During hand immersion, regulate the blood pressure manually using a sphygmomanometer, or using a custom built electro-pneumatic regulator.
Then, place a 35 centimeter tourniquet on the subject's non-dominant upper arm. Instruct the subject to sit comfortably with their palm flat, with fingers spread wide, without touching the edges of the bath, and rate their pain intensity. Then the subject should place their non-dominant hand into a warm, 35 degree Celsius water bath for two minutes.
At one minute and 45 seconds, inflate the blood pressure cuff on their upper arm to 20 millimeters mercury below resting diastolic blood pressure. Then, at two minutes, instruct the subject to move their hand from the warm water bath and directly place it into the cold water bath at a similar depth. As before, the subject should rate their pain response as the time of cold immersion progresses using the electronic Visual Analogue Scale.
After reaching pain tolerance or a time limit of 120 seconds, instruct the subject to remove their arm, and deflate the blood pressure cuff. Provide the subject with a towel to dry their forearm. In order to perform a conditioned pain modulation paradigm, repeat the electrical stimulation task previously described within five minutes after the end of the cold pressor test.
Prior to starting ultraviolet inflammation testing, first turn on the UVB lamp and allow it to warm up for at least ten minutes before use. Be sure to replace the fluorescent tubes after approximately 50 to 100 working hours. Then, begin by determining the subject's minimal erythemic dose, or MED.
Instruct them to stand with their left hand holding their right shoulder. Place the UVB lamp on the right, upper back, shoulder area in direct contact with the skin. Only induce the erythema on even toned, healthy skin.
For the screening visit, apply the UVB exposure based on the subject's Fitzpatrick skin type. Use ascending doses to six different one-by-one centimeter areas of skin on the subject's back to determine the individual UVB dose that produces the first clearly discernible erythema. Then assess the erythemic response 24 hours after the exposure of the six doses.
Next, 24 hours prior to the first task battery, apply a three-by-three centimeter UVB exposure equivalent to the subject's three-fold individual minimal erythema dose to the subject's back. Ensure the UVB exposure produces a homogeneous, well demarcated area of skin erythema, thereby inducing hyperalgesia. After 24 hours, use a three-by-three centimeter thermode to assess the subject's skin thermal detection threshold.
Measure the thermal pain detection threshold on normal skin contralateral to the site of UVB irradiation. Set the temperature initially to 34, then ramp up by 0.5 degrees Celsius per second. Then, repeat this on the side with UVB-irradiated skin.
Record the average pain detection threshold for three consecutive stimuli. The most critical step is for a subject to consistently rate their pain during the repeated measurements. This is overcome by clear and consistent instructions.
Also, a crossover study design, in which subjects serve as their own control, is preferred. The outcome variables defined for a study are seen here. Pain detection threshold, area under the Visual Analogue Scale pain curve, and post-test rating Visual Analogue Scale are end points for the pain tolerance studies.
This figure shows the effect of intravenous analgesics on cold pressor pain tolerance thresholds. Example time courses are shown after 30 minute intravenous administration of placebo, ten milligrams of S-ketamine, three micrograms per kilogram fentanyl, and 300 milligrams phenytoin. Here we see the effect of oral analgesics on cold pressor pain tolerance thresholds.
Example time courses are shown after oral administration of placebo, 100 milligrams of imipramine, 600 milligrams of ibuprofen, and 300 milligrams of pregabalin. Once mastered, performing all the tasks takes approximately 30 minutes if they're performed properly. This makes it possible to repeat a measurement round multiple times throughout one day, without it being too burdensome on the subject.
While attempting the procedure, it's important to remember to minimize interactions with the subjects, except for instructions related to the tasks themselves. Following this procedure, other methods like neurophysiological tests or cognitive tasks can be used to determine drug side effects or other pharmacodynamic effects. For example, respiratory measures and pupillometry can be used to determine side effects of opioids.
After their development, these pain tasks have paved the way for researchers in the field of pain to explore the analgesic potential of drugs with different mechanisms of action.
