Endogenous inhibition of pain and spinal nociception in women with premestrual dysphoric disorder.

The study indicates that women with PMDD do not differ from healthy controls in CPM of pain, and that they do not have distributed CPM of spinal nociception. However, women with PMDD do evidence greater ischemic and electrocutaneous pain senstivity during the late-luteal phase and enhanced spinal nociception during ovulation.

Premenstrual dysphoric disorder (PMDD) involves severe affective and physical symptoms, such as increase in pain, during the late-luteal phase of the menstrual cycle.  Data from the recent studies postulate that women with PMDD also experience heightened premenstrual pain, including headaches  and musculoskeletal pain.  This increase in pain has become the major reason of significant distress, impaired functioning, and disturbed quality of life in women with PMDD. Although pain is a significant symptom in PMDD but only five published studies have used experimental pain to assess pain processing in PMDD. The findings of few studies have suggested the potential differences in pain processing in PMDD. However, it remains unclear what mechanisms cause these discrepancies. Conditioned pain modulation (CPM) is a method that experimentally evaluates endogenous pain inhibition. It includes the application of a tonic painful stimulus (conditioning stimulus) to inhibit pain evoked by a phasic, test stimulus at a distal body site. CPM has been studied extensively in both healthy and clinical populations, However, there have been no investigations assessing CPM in PMDD across the menstrual cycle.

Rationale behind research:

There have been no investigations assessing CPM in PMDD across the menstrual cycle. Thus, this study was conducted to identify the mechanisms that contribute to pain in PMDD

Objective:

To determine whether endogenous inhibition of pain and NFR varies across the mid-follicular, ovulatory, and late-luteal phases of menstrual cycle in women with PMDD.

NOTE: Linear mixed model analysis was used to assess the influence of group and menstrual phase on CPM.

Participants were given instructions on menstrual cycle monitoring and then randomly assigned to one of six testing orders: 1) mid-follicular – ovulatory – late-luteal; 2) mid-follicular – late-luteal – ovulatory; 3) ovulatory – mid-follicular – late-luteal; 4) ovulatory – late-luteal – mid-follicular; 5) late-luteal – mid-follicular – ovulatory; 6) late-luteal – ovulatory – mid-follicular. Participants then tracked their menstrual phases for three cycles. Cycle 1 was used to establish cycle length and ovulation timing. Experimental testing occurred during cycles 2 and 3 (with the exception of participants assigned to a luteal/ovulatory/follicular testing order, for whom the first pain testing session occurred during cycle 1).

Upon arrival participants were then instructed on the use of the Numerical Rating Scale (NRS) to rate pain. Next, sensors were applied to participants for physiological recording. The procedures in the testing session proceeded in the following order: NFR threshold testing, electrocutaneous pain threshold assessment, emotional controls of nociception (ECON), and CPM. At the end of the session, participants were reminded to continue tracking their menstrual phases until all three cycles were completed.

Menstrual cycle monitoring, phase determination and PMDD diagnosis was carried out in the participants.

Study outcomes

NFR threshold and magnitude assessment: The NFR is a spinally-mediated withdrawal reflex primarily elicited by Aδ pain fiber activation following noxious stimulation. NFR and pain thresholds were therefore assessed prior to CPM testing. During CPM testing, NFR magnitude was used as a physiological measure of spinal nociception because the size of the reflex correlates with subjective pain intensity, as well as activity of nociceptive dorsal horn neurons.23,24 The NFR was defined as a mean biceps femoris EMG response in the 90–150 ms post-stimulus interval that exceeded mean EMG activity during the 60 ms pre-stimulus baseline interval by 1.4 standard deviations (SDs). NFR magnitude was converted to Cohen’s d units (d= [mean EMG of 90–150 ms post-stimulation interval – mean EMG of 60 ms pre-stimulation interval]/average SD of EMG from pre- and post-stimulation intervals).

Electrocutaneous pain threshold assessment: Pain threshold was assessed using three ascending– descending staircases of electric stimuli. Stimulus parameters and interstimulus intervals were the same as during NFR testing. Participants rated their pain intensity on the NRS immediately following each stimulus. Pain threshold was defined as the average stimulation intensity (mA) of the four stimuli immediately above and immediately below a rating of 50 on the last two ascending–descending staircases.

CPM of pain and NFR: CPM involves the application of a tonic, painful, conditioning stimulus to dampen pain evoked at a distal (heterotopic) body site by a painful test stimulus. CPM was assessed by delivering four painful electrocutaneous stimulations during the 2 minutes prior to ischemia (baseline), four during the 2 minutes of ischemia, and four during the 2 minutes after (post) the ischemia procedure (12 stimulations in total). The NRS was administered following each stimulus to assess pain. Biceps femoris EMG was recorded throughout the procedure to assess NFR magnitudes. Following the CPM procedure, participants used the NRS to rate the overall pain in response to the blood pressure cuff on their arm (ie, forearm ischemia pain).

Baseline: There were no group differences in any of the demographic or clinical variables.

Outcomes

Ischemia pain ratings: There was a main effect of menstrual phase on ischemia pain ratings following the CPM procedure (F[2, 49.23]=3.35, P=0.04). Ischemia pain ratings were greatest in the PMDD group during the late-luteal phase, compared to the mid-follicular and ovulation phases (P-values<0.05), but mid-follicular pain ratings were not different from ovulation (P=0.35)

Modulation of Pain: There was a significant main effect of CPM phase (F[2, 757.28]=5.20, P=0.01), but there was neither a significant group × CPM phase interaction (F[2, 790.13]=0.25, P=0.78) nor a group × menstrual phase × CPM phase interaction (F[4, 592.54]=1.87, P=0.11). Both HC and women with PMDD demonstrated pain inhibition during the ischemia and post-ischemia phases, relative to baseline (P-values<0.05), but there was no difference between ischemia and post-ischemia (P=0.52). Contrasts for the simple effect of menstrual phase found that the PMDD group rated the electrocutaneous stimulations as more painful during the late-luteal phase compared to the ovulation phase (P=0.02), and there was a trend towards significance compared to the mid-follicular phase (P=0.07). Overall, these data indicate that CPM modulation did not vary by group or menstrual phase. However, there were menstrual phase differences in pain sensitivity across each group, with the PMDD group rating the electrocutaneous stimulations as more painful during the late-luteal phase.

Modulation of NFR magnitude: There was a significant main effect of CPM phase [F(2, 598.38)=3.03, P<0.05] that was qualified by a significant group × CPM phase interaction [F(2, 604.78)=4.22, P=0.02]. The PMDD group exhibited lower NFR magnitude during the ischemia phase vs the pre-ischemia baseline (P=0.001) however, HC did not show NFR modulation during the CPM procedure (P-values>0.16). The main effect of menstrual phase was not significant (P=0.19); however, there was a significant interaction of group × menstrual phase [F(2, 234.45)=4.31, P=0.01]. The PMDD group evidenced an increase in NFR magnitude during the ovulation phase compared to the mid-follicular (P=0.03) and the late-luteal phases (P=0.01). This indicates that PMDD showed modulation of NFR magnitude during CPM, as well as differences in NFR across menstrual cycle phases, while HC did not.

The results of the study indicates that women with PMDD do not differ from healthy controls in CPM of pain, and that they do not have distributed CPM of spinal nociception. However, women with PMDD do evidence greater ischemic and electrocutaneous pain senstivity during the late-luteal phase and enhanced spinal nociception during ovulation. This is consistent with heightened premenstrual pain symptomatology commonly observed in women with PMDD and is supported by studies reporting increased senstivity to experimental pain during the symptomatic phase.

Straneva and his co-authors measured pain threshold and tolerance in response to forearm ischemia in a group of 27 women with PMDD and 27 healthy controls across the follicular and luteal phases of menstrual cycle. Although women with PMDD exhibited a phase-independent hyperalgesia in ischemia pain thresholds and tolerances, ratings of pain intensity and unpleasantness were generally higher during the luteal phase.