Translational issues in precision medicine in neuropathic pain

Figures & data

Table 1. Effects of drugs on spinothalamic wide dynamic range neuronal responses in spinal nerve ligated rats

			Punctate mechanical		Heat		Cold
Receptor	Drug	Brush	Innocuous	Noxious	Innocuous	Noxious	Innocuous	Noxious	Windup	Spontaneous	DNIC
VGSCs	Oxcarbazepine (s.c)^Citation14	↓	↓↓	↓↓	–	–	↓	↓↓	–	↓↓
VGSCs	Licarbazepine (i.pl)^Citation14	↓	↓↓	↓↓	–	–	↓	↓↓	–	↓↓
5-HT2A	Ketanserin (i.th)^Citation58	–	–	↓	–	↓	↓↓	↓↓		–
NET	Reboxetine (i.th)^Citation56,Citation61	–	↓	↓	–	–	–	↓		–	↑↑
TRPM8	M8-an (s.c)^Citation62	–	–	–	–	–	↓↓	↓↓	–
α2δ-1	Pregabalin (s.c)^Citation31,Citation41	↓↓	↓↓	↓↓	–	↓	–	–	–	–
5-HT3	Ondansetron (i.th)^Citation56,Citation58,Citation63	–	↓↓	↓↓	–	↓↓	–	–	–	–	↑↑
Cav2.1/2/3	TROX-1 (i.th & s.c)^Citation50	–	↓↓	↓↓	–	–	–	–	–
OR	Morphine (s.c)^Citation64	–	↓↓	↓↓	↓↓	↓↓		↓↓		↓↓
α2	Clonidine (i.th)^Citation61	↓↓	↓↓	↓↓	↓↓	↓↓	↓↓	↓↓		↓↓
μOR/NET	Tapentadol (s.c)^Citation56,Citation65	↓↓	↓↓	↓↓	↓	↓↓			↓↓		↑↑
Cav2.1/3	Tx3-3 (i.th)^Citation49	↓	↓↓	↓↓	↓	↓↓			↓
A3	MRS5698 (s.c)^Citation66	↓	↓↓	↓↓	↓↓	↓↓			↓↓
VGSCs	Lacosamide (i.th & s.c)^Citation15	↓	–	↓↓	↓	↓↓			↓↓
NMDA	Ketamine (s.c)^Citation67,Citation68		↓↓	↓↓		↓↓			↓↓	–

Examining drug actions on evoked sensory neuronal endpoints reveals three broad groups characterized by predominant inhibitory effects on (1) mechanically and cold-evoked responses, (2) mechanically evoked responses, and (3) all modalities.

↓ = moderately inhibited; ↓↓ = inhibited; ↑↑ = enhanced; – = no/minimal effect; (blank) = not tested; VGSCs = voltage-gated sodium channels; s.c = subcutaneous; i.pl = intraplantar; i.th = intrathecal; NET = norepinephrine transporter; TRPM8 = Transient Receptor Potential Melastatin 8; OR = opioid receptor; A = adenosine.

Figure 1. Sensory profiles of the three-cluster solution for test and replication data sets. Sensory profiles of the three clusters are presented as mean z scores ± 95% confidence interval for (A) the test data set (n = 902) and (B) the validation data set (n = 233). Note that z transformation eliminates differences due to test site, sex, and age. Positive z scores indicate positive sensory signs (hyperalgesia), whereas negative z values indicate negative sensory signs (hypoesthesia and hypoalgesia). Dashed lines: 95% confidence interval for healthy subjects (−1.96 < z < + 1.96). Note that if the mean of a cluster is within the shaded area, this does not imply that it does not differ from a healthy cohort. Values are significantly different from those of healthy subjects if the 95% confidence interval does not cross the zero line. Insets show numeric pain ratings for dynamic mechanical allodynia on a logarithmic scale (0–100) and frequency of paradoxical heat sensation (0–3). Blue symbols: Cluster 1 “sensory loss” (42% in A and 53% in B). Red symbols: Cluster 2 “thermal hyperalgesia” (33% in A and B). Yellow symbols: Cluster 3 “mechanical hyperalgesia” (24% in A and 14% in B). CDT = cold detection threshold; WDT = warm detection threshold; TSL = thermal sensory limen; CPT = cold pain threshold; HPT = heat pain threshold; PPT = pressure pain threshold; MPT = mechanical pain threshold; MPS = mechanical pain sensitivity; WUR = windup ratio; MDT = mechanical detection threshold; VDT = vibration detection threshold; NRS = Numerical Rating Scale; DMA = dynamic mechanical allodynia; PHS = paradoxical heat sensation. Reproduced with permission from Baron et al.⁵ (under a Creative Commons license)

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