Sage Journals: Discover world-class research

Abstract

Background

Greater occipital nerve (GON) blocks are widely used for the treatment of headaches, but quality evidence regarding their efficacy is scarce.

Objective

The objective of this article is to assess the short-term clinical efficacy of GON anaesthetic blocks in chronic migraine (CM) and to analyse their effect on pressure pain thresholds (PPTs) in different territories.

Participants and methods

The study was designed as a double-blind, randomised, placebo-controlled clinical trial. Thirty-six women with CM were treated either with bilateral GON block with bupivacaine 0.5% (n = 18) or a sham procedure with normal saline (n = 18). Headache frequency was recorded a week after and before the procedure. PPT was measured in cephalic points (supraorbital, infraorbital and mental nerves) and extracephalic points (hand, leg) just before the injection (T0), one hour later (T1) and one week later (T2).

Results

Anaesthetic block was superior to placebo in reducing the number of days per week with moderate-or-severe headache (MANOVA; p = 0.027), or any headache (p = 0.04). Overall, PPTs increased after anaesthetic block and decreased after placebo; after the intervention, PPT differences between baseline and T1/T2 among groups were statistically significant for the supraorbital (T0–T1, p = 0.022; T0–T2, p = 0.031) and infraorbital sites (T0–T1, p = 0.013; T0–T2, p = 0.005).

Conclusions

GON anaesthetic blocks appear to be effective in the short term in CM, as measured by a reduction in the number of days with moderate-to-severe headache or any headache during the week following injection. GON block is followed by an increase in PPTs in the trigeminal area, suggesting an effect on central sensitisation at the trigeminal nucleus caudalis.

This trial is registered at ClinicalTrials.gov (NCT02188394).

Keywords

Clinical trial chronic migraine nerve block greater occipital nerve pressure pain thresholds algometry

Introduction

The therapeutic approach to chronic migraine (CM) is a subject of growing interest among headache specialists. The International Classification of Headache Disorders, third edition, beta version (ICHD-3 beta) defines CM as a headache present more than 15 days per month in the last three months, with characteristic migraine features at least eight days per month (1). Each year, 2.5% to 3% of patients with episodic migraine (EM) evolve into CM (2,3). The prevalence of CM in the general population lies between 1.4 and 5% (4,5). Management of patients with CM first relies on the identification and correction of risk factors that predict transformation to CM, and empirical prescription of acute and preventive treatments that are effectively used in EM (6,7). Nevertheless, for many patients this strategy is insufficient and results in poor symptom control (8). Specific trials in patients with CM are sparse, but there is some evidence for the effectiveness of topiramate and other oral medications (9 –11). In addition, botulinum toxin type A has been proved effective as a preventive treatment in CM over the last years (12,13). However, the therapeutic effect of botulinum toxin injections as well as other preventive treatments requires a latency period ranging from a few days to several weeks. This highlights the need for short-term effective treatments that can serve as adjuvant or transitional therapies.

Although the mechanisms underlying the transformation of EM into CM are not completely elucidated, some research suggests a role for central sensitisation (14,15). Repeated peripheral inputs may lead to second and third neuron hyperexcitability in nociceptive pathways, thus causing spontaneous pain, hyperalgesia and allodynia. CM patients seem to have higher grades of central sensitisation than those with EM. Indeed, patients with CM exhibit greater cutaneous allodynia in trigeminal and extra-trigeminal areas than patients with EM (16). Central sensitisation is also reflected in a general decline of mechanical and thermal pain thresholds in patients with migraine compared to healthy individuals (17,18). Some studies have shown lower pain thresholds in CM compared to EM (19), whereas others have not found differences between CM and EM (20,21).

The anatomo-functional convergence of sensory afferents from the C2 spinal nerve and the trigeminal nerve within the trigemino-cervical complex has been well established (22). The greater occipital nerve (GON) carries sensory fibres that originate predominantly at C2, with a cutaneous distribution covering the posterior part of the head. Therefore, GON blocks may alleviate the pain in the trigeminal area by reducing neuronal hyperexcitability at the second-order neuron level (23). GON blocks with local anaesthetics and/or corticosteroids have been employed for decades in the acute and prophylactic treatment of migraine and other headache disorders (24,25). However, only three randomised, placebo-controlled trials examining the effect of GON blocks in patients with migraine have been published (26 –28); these trials had contradictory conclusions and only one of them was focused on CM.

We designed this double-blind, randomised and placebo-controlled clinical trial with the aim of assessing the short-term clinical efficacy of GON anaesthetic blocks in CM. Secondly, we aimed to analyse their short-term effects on pressure pain thresholds (PPTs) in different locations, as a physiopathogenic proof of concept.

Participants and methods

Study design and protocol

This double-blind, randomised and placebo-controlled clinical trial was approved by the Clinical Research Ethics Committee of Hospital Clínico San Carlos (internal code: 11/263) and subsequently registered at ClinicalTrials.gov (NCT02188394).

Patients were recruited sequentially at the Headache Unit of the Neurology Department of Hospital Clínico San Carlos, Madrid, between September 2013 and May 2015. All patients were required to sign an informed consent form prior to randomisation. Allocation of patients to active or placebo treatment was made by restricted randomisation with a computer random number generator by one of the investigators (CFP). The randomised treatment allocation schedule had six blocks. Six patients were included in each block totalling 36 patients.

The study design followed the guidelines of the International Headache Society (IHS) for controlled trials of prophylactic treatment in CM (29), as well as the recommendations of the American Headache Society (AHS) for clinical trials of local anaesthetic blocks in headaches (24). Moreover, we followed the usual recommendations for pressure algometry studies and PTT measurements (30).

The study protocol was scheduled in the following steps (Figure 1): (i) recruitment and patient information (R); (ii) first observational period, with patients’ recordings of headaches in a standard paper diary during one week prior to the intervention; (iii) basal algometry, with PTT measurements immediately before the intervention (T0); (iv) allocated intervention (either sham procedure or anaesthetic blockade); (v) one-hour post-intervention algometry (T1); (vi) second observational period, with patients’ recordings of headaches during one week following the intervention; (vii) one-week post-intervention algometry (T2).

Figure 1.

Study phases for each patient.

Study participants and clinical assessment

Thirty-six patients with CM participated in the study. Inclusion criteria were: (i) female gender; (ii) age 18–65; and (iii) ICHD-3 beta-defined CM (1). Exclusion criteria were: (i) individuals who had been started on an effective preventive medication within the past three months; (ii) medication-overuse headache, as defined by the ICHD-3 beta; (iii) treatment with peripheral nerve blocks, trigger point injections or botulinum toxin injections within the past six months; (iv) known hypersensitivity or allergic reaction to amide-type local anaesthetics; (v) pregnancy or nursing; (vi) history of drug or alcohol abuse; (vii) history of a major psychiatric disorder; (viii) history of neurosurgery or severe head trauma; (ix) history of an unstable medical condition (e.g. cardiovascular, hepatic, renal, endocrine); (x) history of other chronic pain syndromes (e.g. fibromyalgia); (xi) maintenance opioid medication; (xii) State Scale of the State-Trait Anxiety Inventory (STAI-state, Spanish validated version) ≥31 or Beck Depression Inventory (BDI-II, Spanish validated version) ≥19; or (xiii) inability to understand and complete an informed consent or to conduct a proper record of headaches.

Recorded baseline characteristics included age, body mass index (BMI), time since migraine onset, time since CM onset, lateralisation of headache (uni- or bilateral), tenderness of the GON to palpation, presence of aura, use of prophylactic medication (beta-blockers, neuromodulators, antidepressants, flunarizine, angiotensin-converting enzyme (ACE) inhibitors, other), use and frequency of consumption of acute symptomatic medications (simple analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, opioids, other). Prophylactic medication use was stable for three months prior to the study and could not be changed during the study. Patients were asked to keep their usual treatment and pain-managing habits.

Headache diary

The clinical endpoint data were collected from the headache diary. During the pre- and post-intervention weeks, patients were asked to write down all headache episodes along with daily duration and intensity (mild, moderate or severe), as well as any acute medication and its response. Instructions were given to register any relevant migraine trigger, such as menses or psychological stress. Open questions were asked regarding any adverse events.

PPT assessment

PPT measurements were performed by a single blinded investigator (PN), with a Fischer pressure analogue algometer (Pain Diagnosis and Treatment Inc, Great Neck, NY, USA). This device consists of a round rubber disk (area: 1 cm²) attached to a pressure gauge. The gauge displays values in kg/cm², ranging from 0 to 10 kg, with 0.1 kg intervals. PPT is defined as the minimal amount of pressure at which a sense of pressure first changes to pain.

Patients were told to avoid symptomatic medication 12 hours prior to the examination. The evaluation was carried out in a supine, relaxed position, and only if patients were headache free or were suffering from a mild headache. PPTs were measured bilaterally and symmetrically in several cephalic and extracephalic points: (i) supraorbital nerve emergence, at the supraorbital notch (trigeminal V1 branch); (ii) infraorbital nerve exit, at the infraorbital foramen (trigeminal V2 branch); (iii) mental nerve at its exit through the mental foramen (trigeminal V3 branch); (iv) dorsum of hand, at the midpoint of the bone length between the second and third metacarpal bones; (v) tibialis anterior muscle, three fingers’ breadth lateral to the tibial crest, over the muscle mass. Three consecutive PPT measurements at intervals of 20 seconds were obtained by applying continuous pressure with the algometer at approximately a rate of 1 kg/cm²/s. For each point, the mean score of the three trials was used for further analysis. This technique has shown a high intra- and inter-rater reliability (31). Finally, the PPT value for each anatomic region was derived from the average of right and left measurements.

Intervention

Patients were equally randomised to receive either active treatment using a local anaesthetic or placebo. The patients were injected at the point 3 cm below and 1.5 cm lateral to the inion. In each patient, 2 ml of local anaesthetic (bupivacaine 0.5%) or placebo (normal saline) was injected at both left and right sites using a 30G needle. A single trained investigator with ample experience (AAS) performed all the injections blinded; to ensure the blinding, syringes were loaded out of sight by a second investigator (MLC). Patients were asked to remain in the examination room for 10 minutes after the procedure so as to record early adverse reactions.

Outcome measures

Based on the IHS recommendations for clinical trials in CM (29), we defined our primary outcome as reduction in mean frequency of moderate or severe headache calendar days – quantified as days with headache lasting more than four hours, with moderate or severe intensity at its maximum, or of any duration or intensity if relieved by triptans or ergots. As secondary outcomes we considered: (i) response rate, defined as the proportion of patients showing a reduction in moderate or severe headache days of 50% or greater; (ii) reduction in mean frequency of all headache days of any intensity – quantified as days with headache lasting more than four hours or any duration if relieved by triptans or ergots; (iii) reduction in mean number of days with acute medication consumption, and (iv) increase in mean PPTs measured in each of the cephalic and extracephalic points.

Statistical analysis

Sample size calculation was based on a preliminary study with 18 patients. For an alpha level of 0.05, and a desired power of 80%, a sample size of 36 patients (18 patients per group) was determined.

We performed an intention-to-treat analysis. Basal comparisons between groups were established by clinical relevance according to Consolidated Standards of Reporting Trials (CONSORT) recommendations (32). The reliability of algometry measures at each point was analysed by the intra-class correlation coefficient (ICC). The absence of significant differences between PPT measurements of both sides was demonstrated with the paired t-test. Outcome measures between groups were compared using multivariate analysis of variance (MANOVA) for repeated measures, with time as intra-subject factor and group as inter-subject factor. The effect size (absolute reduction) with 95% confidence interval (95% CI) was estimated using the paired-samples t-test. A model adjusted for the use of prophylactic therapy was calculated using logistic regression. The response rate odds ratio (OR) with a 95% CI was also calculated. Of the patients treated with anaesthetic, we assessed the weight of GON tenderness on response rate using a logistic model. All variables fulfilled the assumptions of parametric data after testing of normality and homogeneity of variance. Type I error cut-off for statistical significance was set at 0.05 (p < 0.05) – no corrections to control for family-wise error were applied. Statistical analysis was performed using the SPSS software package, 18.0 version (SPSS Inc, Chicago, IL, USA).

Results

Demographic and baseline clinical characteristics

During the study period, 57 patients referred to the Headache Unit by other neurologists were assessed for eligibility (Figure 2, CONSORT flow diagram). Overall, 21 patients were excluded before randomisation: 10 did not consent to participate in the study, six had a ≥31 STAI-state score and/or a ≥19 BDI-II score, and five presented with moderate or severe headache on the day of basal algometry (T0).

Figure 2.

Participant flow diagram.

The 36 patients were randomly allocated into two 18-patient groups. No patients were lost to follow-up. Table 1 shows the baseline demographic and clinical characteristics of the active and placebo groups.

Table 1.

Baseline demographic and clinical characteristics^a.

Demographic and clinical parameters	Anaesthesia (n = 18)	Placebo (n = 18)
Age, y	35.7 (8.6)	35.9 (13.4)
BMI, kg/m²	25.8 (6.8)	23.6 (4.2)
Time since migraine onset, y	20 (10.8–25.3)	16 (11.5–31.0)
Time since CM onset, y	1 (0.3–3.8)	2 (0.7–4.0)
Aura	12 (66.7%)	10 (55.6%)
Headache location:
Left	2 (11.1%)	1 (5.5%)
Right	1 (5.5%)	1 (5.5%)
Bilateral	15 (83.3%)	16 (88.9%)
GON tenderness	12 (66.7%)	14 (77.8%)
Prophylactic treatment^b:	3 (16.7%)	10 (55.6%)
Beta-blockers	2 (11.1%)	3 (16.7%)
Neuromodulators	1 (5.5%)	5 (27.8%)
Antidepressants	0	2 (11.1%)
Flunarizine	0	1 (5.5%)
ACE inhibitors	0	1 (5.5%)
Symptomatic acute treatment:
NSAID	15 (83.3%)	14 (77.8%)
Triptans	7 (38.9%)	10 (55.6%)
Acetaminophen or metamizole	1 (5.5%)	8 (44.4%)
Opioids	0	2 (11.1%)

Age and BMI are expressed as mean and standard deviation (SD); time since migraine and CM onset are expressed as median and interquartile range (IQR); qualitative variables are presented as absolute values and percentages.

Two patients in the placebo group were taking a combination of two preventives: flunarizine plus venlafaxine (n = 1), and nebivolol plus topiramate (n = 1).

BMI: body mass index; CM: chronic migraine; GON: greater occipital nerve; ACE: angiotensin-converting enzyme; NSAID: nonsteroidal anti-inflammatory drugs.

Demographic and clinical characteristics were similar in both groups (Table 1). Ages ranged from 18 to 59 years in the whole cohort, with a mean of 35.8 years (standard deviation, SD, 11.1). The median time since migraine onset was 17.5 years (interquartile range, IQR 11.25–25.75), and the median time since becoming chronic was two years (IQR 0.5–3.75). A history of aura was present in 61.1%, with a similar proportion in both study groups. Mean BMI was 24.7 (SD, 5.7), and was comparable in the two groups. GON tenderness was found in 72.2%, without important differences between groups. Acute medication use was relatively similar in both groups, although triptans, simple analgesics and opioids were more commonly used in the placebo group. The only meaningful difference between groups was the number of patients on prophylactic treatment at baseline, with a proportion of 55.6% for the placebo group and 16.7% for the active group. However, drug class and dosage had remained stable for more than three months in all of the cases. Moreover, all baseline calendar variables (pre-intervention week) were comparable in both groups (Table 2).

Table 2.

Clinical efficacy variables.

	Pre- intervention (1 week)	Post- intervention (1 week)	Intra-group differences	p value between groups
Number of moderate or severe headache days:
Anaesthesia	4 (1.9)	2 (1.6)	–2 (–2.7; −1.3)	0.027
Placebo	4 (2.2)	3.6 (2.1)	–0.4 (–1.4; 0.5)	0.027
Number of headache days of any intensity:
Anaesthesia	4.9 (1.9)	3.4 (2.6)	–1.5 (–2.3; −1.3)	0.04
Placebo	4.6 (2.1)	4.5 (2.2)	–0.1 (–0.9; 0.7)	0.04
Number of days with acute medication consumption:
Anaesthesia	3.9 (2.1)	2.5 (1.9)	–1.4 (–2.4; −0.5)	0.7
Placebo	4.3 (1.7)	3.4 (2)	–0.9 (–1.7; −0.1)

Pre- and post-intervention parameters are expressed as mean and standard deviation (SD); intra-group differences are expressed by the mean effect size with a 95% confidence interval.

Clinical efficacy and safety

The clinical outcome data are summarised in Table 2. Significant differences between study groups were found in the primary outcome variable (reduction in mean number of moderate or severe headache calendar days) and in one of the secondary outcome clinical variables (reduction in mean number of headache days of any intensity). For the primary outcome measure, the intra-group difference was an absolute reduction of −2 days (95% CI −2.7, −1.3) in the group treated with anaesthesia compared to −0.4 days (95% CI −1.4, 0.5) in the placebo group (p = 0.027). The difference was also significant in the reduction of any-intensity-headache calendar days, with a smaller effect size in both groups (−1.5 days in anaesthesia group vs. −0.1 in placebo group; p = 0.04). There were no significant differences between groups in the number of days with acute medication consumption. Nevertheless, the reduction was greater in the anaesthetic group (−1.4 vs. −0.9; p = 0.7).

Five patients in each group reported relevant migraine triggers during the pre-intervention week (three with menstruation and two with psychological stress in the active group; two with menstruation and three with psychological stress in the placebo group). During the post-intervention week, six patients identified triggers in the active group (three with menstruation and three with psychological stress) and four in the placebo group (three with menstruation and one with psychological stress).

Few adverse reactions were reported in both groups. Immediately after the intervention, two patients in the placebo group and one in the active group experienced pre-syncope. All patients responded to physical measures within 10 minutes. In addition, two patients in the placebo group and one in the active group had a transitory stinging sensation at the puncture site lasting less than five minutes.

The proportion of patients showing ≥ 50% reduction in moderate or severe headache days – i.e. the response rate – was higher in the group treated with anaesthetic than in the group treated with placebo (55.6% vs. 27.8%; OR 3.25, 95% CI 1.36–7.78, p = 0.008). Logistic regression analysis adjusted for the use of prophylactic therapy confirmed this finding (OR 2.92, 95% CI 1.19–7.15, p = 0.019).

Of patients treated with anaesthetic block, those with GON hypersensitivity had 50% less response to the intervention than their counterparts, which was statistically non-significant (p = 0.424).

Changes in PPTs

Algometry measurement ICC was excellent (0.8–0.98). Compared to baseline, mean PPTs one hour after the intervention (T0–T1) increased in patients treated with anaesthetic block and decreased in the control group, both in cephalic and extracephalic points; however, the differences between groups were statistically significant only for the supraorbital (+0.05 vs. −0.12 kg/cm²; p = 0.022) and infraorbital sites (+0.08 vs. −0.13 kg/cm²; p = 0.013). Similar results were found for mean PPTs one week after the intervention (T0–T2); again, only the variations at the supraorbital (+0.06 vs. −0.15 kg/cm²; p = 0.031) and infraorbital sites (+0.11 vs. −0.24 Kg/cm²; p = 0.005) were significantly different between groups. Table 3 summarises the changes in all PPTs.

Table 3.

Pressure pain thresholds (PPTs)^a.

	T0	T1	T2	Change T0–T1	p value between groups	Change T0–T2	p value between groups
Supraorbital
Anaesthesia	1.42 (0.3)	1.47 (0.4)	1.48 (0.4)	0.05 (–0.06; 0.16)	0.022	0.06 (–0.1; 0.22)	0.031
Placebo	1.41 (0.3)	1.3 (0.4)	1.26 (0.3)	–0.12 (–0.22; −0.02)	0.022	–0.15 (–0.27; −0.03)	0.031
Infraorbital
Anaesthesia	1.58 (0.3)	1.66 (0.4)	1.69 (0.4)	0.08 (–0.05; 0.21)	0.013	0.11 (–0.08; 0.3)	0.005
Placebo	1.74 (0.5)	1.6 (0.5)	1.5 (0.5)	–0.13 (–0.25; −0.02)	0.013	–0.24 (–0.38; −0.09)	0.005
Mental
Anaesthesia	1.73 (0.5)	1.8 (0.5)	1.85 (0.5)	0.08 (–0.1; 0.25)	0.098	0.13 (–0.13; 0.38)	0.065
Placebo	1.78 (0.5)	1.68 (0.5)	1.62 (0.5)	–0.1 (–0.23; 0)	0.098	–0.16 (–0.36; 0)	0.065
Hand
Anaesthesia	2.73 (0.9)	2.8 (0.8)	2.97 (0.9)	0.08 (–0.16; 0.32)	0.307	0.24 (–0.1; 0.59)	0.128
Placebo	2.84 (0.9)	2.75 (0.9)	2.68 (0.9)	–0.09 (–0.35; 0.2)	0.307	–0.16 (–0.59; 0.3)	0.128
Leg
Anaesthesia	3.65 (1.2)	3.67 (1.2)	4 (1.2)	0.03 (–0.34; 0.39)	0.126	0.32 (–0.24; 0.88)	0.066
Placebo	3.74 (1.4)	3.41 (1.2)	3.4 (1.1)	–0.33 (–0.64; −0.02)		–0.34 (–0.82; 0.1)

PPT values were derived from the average of right and left measurements; they are expressed as kg/cm².

Pre- and post-intervention parameters are expressed as mean and standard deviation (SD); intra-group differences are expressed by the mean effect size with a 95% confidence interval.

Discussion

This clinical trial has proven that GON block can be clinically effective in CM as soon as a week after the intervention, resulting in a reduction in the number of days with headache and the number of weekly moderate and severe headaches. It also provides some evidence to the proposition that it can alleviate central sensitisation occurring in CM – trigeminal (V1 and V2) pain thresholds were significantly higher after anaesthetic GON block, and not so with placebo. The safety of this procedure has been ratified once more by the absence of relevant side effects.

Traditionally, the treatment of migraine through GON blocks has relied on observational studies (33 –37) as controlled clinical trials have been scarce. In 2001, Piovesan et al. carried out the first double-blind clinical trial against placebo for GON block as a preventive treatment in migraine (26). A sample of 37 patients with EM and low or moderate monthly frequency of attacks (mean 3.6 days per month, range 1–8) underwent a sham procedure and GON block in a cross-over design, with a 30-day interval between interventions. The first group (n = 20) received bupivacaine 0.5% on the first visit and normal saline on the second; the sequence was inverted for the second group (n = 17). Although there were no statistically significant differences in the number or duration of migraine episodes between interventions, the first group experienced a significant reduction in migraine episode intensity during the 60-day follow-up.

In 2015, Dilli et al. published a randomised, double-blind clinical trial comparing bupivacaine GON block vs. placebo in frequent EM (at least one episode per week) and CM (27). Patients received either 2.5 ml of bupivacaine 0.5% and 0.5 ml (20 mg) of methylprednisolone (n = 33), or 2.75 ml saline and 0.25 ml of lidocaine 1% (n = 30). No statistically significant reduction in number of moderate-severe headaches was found in any group after four weeks. However, this study included patients with CM and EM; furthermore, GON block was performed once, in contrast to other studies that performed GON block more than once. Moreover, a small amount of anaesthetic was included in the placebo intervention (38,39).

In the same year, Inan et al. carried out a randomised, double-blind clinical trial to assess GON block effectiveness against placebo in a sample of 84 patients with CM (28). Half received GON block with 1.5 ml bupivacaine 0.5% diluted in 1 ml of saline whilst the other half underwent a sham procedure with saline; the intervention was performed once a week during four weeks. After this, all patients were treated with monthly bupivacaine GON blocks for two months; 72 patients completed the study period. In this cornerstone study, GON block was deemed safe and effective in CM with a statistically significant reduction in headache severity, duration and monthly frequency.

After the latter contribution and some other observational studies (35 –37), there is increasing recognition of the possible role of GON blocks in CM as a means to reduce the number, duration and intensity of the attacks, lasting several weeks or months after the intervention. The scope of our study was to analyse the clinical outcome during the first week, concluding that GON block significantly reduces the number of moderate-to-severe headaches (and total number of headaches), at least in the short term. GON tenderness to palpation did not predict a favourable response, even though this clinical finding has been used by some practitioners as a selection criterion for the performance of GON blocks (40); this is in line with an open-label study that could not find an association between the degree of tenderness and treatment outcome in patients with CM (36). Otherwise, we were not able to find any effect of GON blocks on acute medication consumption; however, this could be explained by the exclusion of patients with medication overuse, or the low response rate of chronic pain to symptomatic treatments.

It is generally accepted that GON block acts on headache by modulation of the nociceptive afferences that reach the trigeminal nucleus caudalis. The trigeminal spinal nucleus neurons that lie within the upper cervical spine are functionally and anatomically related to the sensory neurons that innervate the occipital region (22). It has been experimentally proven that trigeminal and occipital afferents converge on the trigeminal-cervical complex, providing the rationale for the sensory GON feedback on the integration of nociceptive information from trigeminal areas (41,42). In fact, unilateral GON block increases the latency and diminishes the amplitude of the R2 response of the blink reflex when stimulating the ipsilateral area in healthy individuals (43). In our patients GON block was followed by an increase in PPTs over the trigeminal area, also suggesting that GON block may interrupt nociceptive stimuli reaching the trigeminal-cervical nucleus. Interestingly, when comparing the changes in PPT values across groups, statistically significant differences were found over the supraorbital (V1) and infraorbital (V2) nerves. However, the absolute variations in PPT values were small, so these findings should be taken with caution.

In our study, GON block reveals itself as an effective therapeutic measure against CM. Due to the long latency period of common preventive treatments, GON block would be most useful as an adjuvant, acting as a bridge between the start of these measures and the onset of their effectiveness. Sample size is the main drawback in our study; many of the non-significant differences found in our study – e.g. PPT changes over different locations – could be due to an underpowered comparison. Additionally, the short follow-up period limits any conclusion to the immediate week after the intervention. Finally, our results cannot be translated into the whole population with CM, as we excluded from our sample male patients, patients whose worsening was temporally related to medication overuse, patients with severe headache at the time of intervention and patients with common comorbidities such as anxiety and depression.

In conclusion, GON block can effectively control the number of headaches in women with CM in the short term. This procedure can also increase pain thresholds as recorded via algometry in the trigeminal region, possibly through the modulation of pain afferents at the trigeminal nucleus caudalis. GON block could be used as an adjuvant in those patients that have been started on preventive medication, to provide pain control during the latency period. New and thorough clinical trials are needed to confirm our findings and establish the indications for GON block in CM.

Clinical implications

Anaesthetic greater occipital nerve (GON) block seems effective in the short term for chronic migraine, as measured by a reduction in the number of days with moderate-to-severe headache or any headache during the week following injection.

GON block is followed by an increase in pressure pain thresholds (PPTs) at the trigeminal area, suggesting an effect on central sensitisation at the trigeminal nucleus caudalis.

Anaesthetic GON block may be useful as a bridging therapy, covering the latency period of established preventive therapies.

Footnotes

Acknowledgement

This study was presented in part at the 17th Congress of the International Headache Society (Valencia, Spain, 14–17 May 2015).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders. 3rd ed (beta version). Cephalalgia 2013; 33: 629–808.

Bigal

Serrano

Buse

et al.

Acute migraine medications and evolution from episodic to chronic migraine: A longitudinal population-based study. Headache 2008; 48: 1157–1168.

Lipton

. Tracing transformation: Chronic migraine classification, progression, and epidemiology. Neurology 2009; 72(Suppl 5): S3–S7.

Natoli

Manack

Dean

et al.

Global prevalence of chronic migraine: A systematic review. Cephalalgia 2010; 30: 599–609.

Buse

Manack

Fanning

et al.

Chronic migraine prevalence, disability, and sociodemographic factors: Results from the American Migraine Prevalence and Prevention Study. Headache 2012; 52: 1456–1470.

Carod-Artal

. Tackling chronic migraine: Current perspectives. J Pain Res 2014; 7: 185–194.

Weatherall

. The diagnosis and treatment of chronic migraine. Ther Adv Chronic Dis 2015; 6: 115–123.

Rothrock

. Treatment-refractory chronic migraine: The ogre emerges from the shadows. Headache 2009; 49: 631–633.

Diener

Bussone

Van Oene

et al.

Topiramate reduces headache days in chronic migraine: A randomized, double-blind, placebo-controlled study. Cephalalgia 2007; 27: 814–823.

10.

Silberstein

Lipton

Dodick

et al.

Efficacy and safety of topiramate for the treatment of chronic migraine: A randomized, double-blind, placebo-controlled trial. Headache 2007; 47: 170–180.

11.

Sun-Edelstein

Rapoport

. Update on the pharmacological treatment of chronic migraine. Curr Pain Headache Rep 2016; 20: 6–6.

12.

Aurora

Dodick

Turkel

et al.

Onabotulinumtoxin A for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 2010; 30: 793–803.

13.

Diener

Dodick

Aurora

et al.

Onabotulinumtoxin A for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 2010; 30: 804–814.

14.

Aurora

. Spectrum of illness. Understanding biological patterns and relationships in chronic migraine. Neurology 2009; 72(Suppl 1): S8–S13.

15.

Mathew

. Pathophysiology of chronic migraine and mode of action of preventive medications. Headache 2011; 51(Suppl 2): 84–92.

16.

LoPinto

Young

Ashkenazi

. Comparison of dynamic (brush) and static (pressure) mechanical allodynia in migraine. Cephalalgia 2006; 26: 852–856.

17.

Andersen

Petersen

Svendsen

et al.

Pressure pain thresholds assessed over temporalis, masseter, and frontalis muscles in healthy individuals, patients with tension-type headache, and those with migraine: A systematic review. Pain 2015; 156: 1409–1423.

18.

Schwedt

Zuniga

Chong

. Low heat pain thresholds in migraineurs between attacks. Cephalalgia 2015; 35: 593–599.

19.

Kitaj

Klink

. Pain thresholds in daily transformed migraine versus episodic migraine headache patients. Headache 2005; 45: 992–998.

20.

Grossi

Chaves

Gonçalves

et al.

Pressure pain threshold in the craniocervical muscles of women with episodic and chronic migraine: A controlled study. Arq Neuropsiquiatr 2011; 69: 607–612.

21.

Schwedt

Krauss

Frey

et al.

Episodic and chronic migraineurs are hypersensitive to thermal stimuli between migraine attacks. Cephalalgia 2011; 31: 6–12.

22.

Goadsby

Bartsch

The anatomy and physiology of the trigeminocervical complex. In: Fernández de las Peñas

Arendt-Nielsen

Gerwin

(eds). Tension-type and cervicogenic headache: Pathophysiology, diagnosis and management, Sudbury: Jones and Barlett, 2010, pp. 109–116.

23.

Ashkenazi

Levin

. Greater occipital nerve block for migraine and other headaches. Is it useful? Curr Pain Headache Rep 2007; 11: 231–235.

24.

Ashkenazi

Blumenfeld

Napchan

et al.

Peripheral nerve blocks and trigger point injections in headache management – a systematic review and suggestions for future research. Headache 2010; 50: 943–952.

25.

Blumenfeld

Ashkenazi

Napchan

et al.

Expert consensus recommendations for the performance of peripheral nerve blocks for headaches – a narrative review. Headache 2013; 53: 437–446.

26.

Piovesan

Werneck

Kowacs

et al.

Bloqueio anestésico do nervo occipital maior na profilaxia da migrânea. Arq Neuropsiquiatr 2001; 59: 545–551.

27.

Dilli

Halker

Vargas

et al.

Occipital nerve block for the short-term preventive treatment of migraine: A randomized, double-blinded, placebo-controlled study. Cephalalgia 2015; 35: 959–968.

28.

Inan

Karadas

et al.

Greater occipital nerve blockade for the treatment of chronic migraine: A randomized, multicenter, double-blind, and placebo-controlled study. Acta Neurol Scand 2015; 132: 270–277.

29.

Silberstein

Tfelt-Hansen

Dodick

et al.

Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. Cephalalgia 2008; 28: 484–495.

30.

Ylinen

Nykanen

Kantiainen

et al.

Evaluation of repeatability of pressure algometry on the neck muscles for clinical use. Man Ther 2007; 12: 192–197.

31.

Chesterson

Sim

Wright

et al.

Inter-rater reliability of algometry in measuring pressure pain thresholds in healthy humans, using multiple raters. Clin J Pain 2007; 23: 760–766.

32.

Schulz

Altman

Moher

et al.

CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c332–c332.

33.

Gawel

Rothbart

. Occipital nerve block in the management of headache and cervical pain. Cephalalgia 1992; 12: 9–13.

34.

Caputi

Firetto

. Therapeutic blockade of greater occipital and supraorbital nerves in migraine patients. Headache 1997; 37: 174–179.

35.

Afridi

Shields

Bhola

et al.

Greater occipital nerve injection in primary headache syndromes – prolonged effects from a single injection. Pain 2006; 122: 126–129.

36.

Weibelt

Andress-Rothrock

King

et al.

Suboccipital nerve blocks for suppression of chronic migraine: Safety, efficacy, and predictors of outcome. Headache 2010; 50: 1041–1044.

37.

Saracco

Valfrè

Cavallini

et al.

Greater occipital nerve block in chronic migraine. Neurol Sci 2010; 31(Suppl 1): S179–S180.

38.

Charleston

4th . One occipital nerve block for the short-term prevention of migraine? Cephalalgia 2015; 35: 1036–1037.

39.

Solomon S. Greater occipital nerve blocks as migraine therapy: A discussion of two recent randomized, double-blinded, placebo-controlled clinical trials. Cephalalgia. 2016; 36: 1094.

40.

Tobin

Flitman

. Occipital nerve blocks: When and what to inject? Headache 2009; 49: 1521–1533.

41.

Goadsby

Zagami

. Stimulation of the superior sagittal sinus increases metabolic activity and blood flow in certain regions of the brainstem and upper cervical spinal cord of the cat. Brain 1991; 114(Pt 2): 1001–1011.

42.

Piovesan

Kowacs

Tatsui

et al.

Referred pain after painful stimulation of the greater occipital nerve in humans: Evidence of convergence of cervical afferences on trigeminal nuclei. Cephalalgia 2001; 21: 107–109.

43.

Busch

Jakob

Juergens

et al.

Functional connectivity between trigeminal and occipital nerves revealed by occipital nerve blockade and nociceptive blink reflexes. Cephalalgia 2006; 26: 50–55.

Short-term effects of greater occipital nerve blocks in chronic migraine: A double-blind,randomised,placebo-controlled clinical trial

Abstract

Background

Objective

Participants and methods

Results

Conclusions

Keywords

Introduction

Participants and methods

Study design and protocol

Study participants and clinical assessment

Headache diary

PPT assessment

Intervention

Outcome measures

Statistical analysis

Results

Demographic and baseline clinical characteristics

Clinical efficacy and safety

Changes in PPTs

Discussion

Clinical implications

Footnotes

Acknowledgement

Declaration of conflicting interests

Funding

References