Table 1. ʻInhibitoryʼ Test Paradigms: Study Design.
| [Ref.] First Author | Year | Study Design | Primary Objective △ | Secondary Objective △ | Oxford Quality Score |
|---|---|---|---|---|---|
| ʻINHIBITORYʼ TEST PARADIGMS | |||||
| Conditioned Modulation Models | |||||
| [1] Willer JC | 1980 | DB, R, PC, 3-WX | Effect of Nx on stress-induced analgesia | NRR | 2 |
| [2] Willer JC | 1981 | DB, R, PC, 3-WX | Effect of Nx in stress-induced analgesia: pain reflexes | Effect of naloxone on development of hyperalgesia | 2 |
| [3] Pertovaara A | 1981 | DB, PC | Effect of Nx on dental pain threshold during non-painful high-frequency TENS | NRR | 1 |
| [4] Pertovaara A | 1982 | DB, PC | Effect of Nx on ischemia-induced pain reduction | Effect of naloxone on ischemia-induced changes in thermal sensitivity | 2 |
| [5] Willer JC | 1982 | DB, PC, | Effect on Nx on the depression on the nociceptive blink reflex induced by high frequency conditioning stimulation | NRR | 1 |
| [6] Pertovaara A | 1982 | DB, R, CB, PC, 2-WX | Effect of Nx on dental pain threshold during non-painful low-frequency TENS | NRR | 1 |
| [7] Buchsbaum MS | 1983 | DB, PC, 3-WX | Effect of Nx on pain sensitivity (assessed by EPs) before and after repeated electrical stimulation | NRR | 2 |
| [8] Jungkunz G | 1983 | DB, R, PC, 4-PG | Effect of Nx on cold pressor induced changes in electrical pain thresholds | Effect of naloxone on mentally stress induced changes in electrical pain thresholds | 3 |
| [9] Janal M | 1984 | DB, R, PC, CB | Effect of Nx on thermal and ischemic responses after exercise | NRR | 2 |
| [10] Willer JC | 1986 | DB, R, PC, 4-WX | Effect of Nx on stress-induced changes in nociceptive flexion reflex threshold | NRR | 2 |
| [11] Ernst M | 1986 | DB, PC, 2-WX | Effect of Nx on habituation to repeated noxious stimuli | NRR | 1 |
| [12] Willer JC | 1986 | DB, R, PC, 4-WX | Effect of Nx on habituation to repeated stress stimuli | Effect of naloxone on autonomic parameters during repeated stress stimuli | 2 |
| [13] Olausson B | 1986 | DB, PC, 2-WX, 4-SX | Effect of Nx on dental pain thresholds following low-frequency TNS | Effect of Nx on dental pain thresholds following muscular exercise | 2 |
| [14] Willer JC | 1990 | DB, R, PC, 2-WX | Effect of Nx on DNIC assessed by the nociceptive flexion reflex | NRR | 2 |
| [15] Poulsen L | 1996 | DB, R, PC, 2-WC, 4-SX | Effect of Nx on DNIC assessed by the nociceptive flexion reflex in extensive and poor metabolizers of sparteine (CYP2D6) | Effect of Nx on pain ratings during cold pressor test in extensive and poor metabolizers of sparteine (CYP2D6) | 2 |
| [16] Edwards RR | 2004 | DB, R, PC, 2-WX | Effect of Nx on DNIC | Effect of Nx on the relationship of cardiovascular reactivity and DNIC | 2 |
| [17] Julien N | 2006 | DB, R, PC, 4-WX | Effect of Nx on spatial summation induced activation of endogenous pain inhibitory system | NRR | 2 |
| [18] Robertson LJ | 2008 | DB, PC, 2-WX | Local effect of Nx on thermal hyperalgesia after a burn injury modified by repeated cold water immersions | NRR | 1 |
| [19] Rennefeld C | 2010 | DB, PC, 8-S | Effect of Nx on habituation to repeated pain stimuli | NRR | 1 |
| [20] Leonard G | 2010 | DB, R, PC, CB, 3-WX, 2-D | Effect of Nx on high-frequency TENS | NRR | 3 |
| [21] Sprenger C | 2011 | DB, R, PC, 2-WX, CB | Effect of Nx on HNCS ¤ induced by CWIT and evaluated by behavioral responses | Effect on Nx on HNCS ¤ induced by CWIT and evaluated by BOLD responses | 3 |
| [22] King CD | 2013 | DB, R, PC, 2-WX | Effect of NTx on CPM | NRR | 3 |
| Repetitive Transcranial Magnetic Stimulation Models | |||||
| [23] de Andrade DC | 2011 | DB, R, PC, SC, 2-WX, 3-PG | Effect of Nx on DLPFC/PMC- and M1-targeted repetitive transcranial magnetic stimulation induced analgesia | NRR | 3 |
| [24] Taylor JJ | 2012 | DB, R, PC, SC, 2x2-WX | Effect of Nx on LDPFC-targeted repetitive transcranial magnetic stimulation induced analgesia | NRR | 4 |
| [25] Taylor JJ | 2013 | DB, R, PC, SC, 2x2-WX | Effect of Nx on LDPFC-targeted repetitive transcranial magnetic stimulation induced analgesia | NRR | 5 |
△ Objectives related to the specific perspectives of the review.
¤ HNCS in man, DNIC in animals (the authors’ terminology [21]).
BI = first-degree burn injury; BOLD = blood-oxygen-level dependent contrast imaging; BTS = brief thermal sensitization; CB = counterbalanced; CPTT = cold pressor test; DB = double-blind; CYP2D6 = cytochrome P450 2D6 enzyme; CPM = conditioned pain modulation; DLPFC/PMC = right dorsolateral–prefrontal cortex premotor cortex (see LDPFC); DNIC = diffuse noxious inhibitory controls; EP = [somatosensory] evoked potentials; EPT = electrical pain threshold; EPIS = endogenous pain inhibitory system; fMRI = functional magnetic resonance imaging; HNCS = heterotopic noxious conditioning stimulations; IDES = intradermal electrical stimulation (rectangular, 0.5 ms duration, 2 Hz, high density); LDPFC = left dorsolateral prefrontal cortex; M1 = primary motor cortex; NFR = nociceptive flexion reflex; NRR = not relevant for the review; NTx = naltrexone; Nx = naloxone; OIH = opioid-induced hyperalgesia; R = randomized; PC = placebo-controlled; SB = single-blind; SBP = systolic blood pressure; SC = sham-controlled; SHA = secondary hyperalgesia area; SOWS = subjective opioid withdrawal scale; SSEP = EP; TCI = target-controlled infusion; TDES = transdermal electrical stimulation (low density); TENS = transcutaneous electrical nerve stimulation; X = cross-over (side to side); 2-D/3-D = two-/two-dose; 2-WX /3-WX/4-WC = two-/three-/four-way cross-over; 3-SX/4-SX/5-SX/6-SX = three-/four-/five-/six-session cross-over study; 8-S = eight session study; 2-PG/3-PG/4-PG/6-PG = two/three/four/six parallel-groups; 2x2-WX = 2 parallel groups each with a 2 way-cross over design.