Abstract
Background
For patients suffering from primary or metastatic cancer above the middle thoracic vertebrae, refractory pain management still remains a great challenge. Theoretically, inserting a catheter tip into the cisterna magna may be a promising solution. However, at present, there have been no reliable data regarding this novel technique. We therefore investigated the efficacy and safety of an advanced approach for pain relief in a specific population.
Methods
Thirty participants from two hospitals received the intrathecal deliveries of opioid to either one of two sites: cisterna magna (n = 15) or lower thoracic region (n = 15). Pain relief (visual analogue scale, VAS), quality of life (short form (36) health survey, SF-36) as well as depression (self-rating depression scale, SDS) were assessed in the follow-up visits and compared between the two groups.
Results
Patients receiving intrathecal morphine delivery to cisterna magna achieved greater pain improvement indicated as significant decrease of VAS scores at day 1 and 7, and achieved better improvement in physical function (day 7 and 30), role physical (day 7 and 30), body pain (day 7, 30 and 90), general health (day 7, 30 and 90), vitality (day 7, 30 and 90), social function (day 90), role emotional (day 7 and 90), mental health (day 7, 30 and 90) and SDS (day 1 and 7).
Conclusions
Intrathecal morphine delivery to cisterna magna might be an effective and safe technique for patients suffering from cancer at the middle thoracic vertebrae or above to control refractory pain. Trial registration: No. ChiCTR-ONN-17010681.
Keywords: cancer pain, interventional pain management, palliative care, psychological aspects of pain
Introduction
Pain is one of the most common and distressing symptoms for cancer patients. It occurs in 67% of patients suffering from advanced or terminal cancer.1 Recently, there has been increasing attention to therapies for cancer pain related to its catastrophic outcome to quality of life.2–4 Since the adoption of World Health Organization (WHO) guidelines related to “ladder” of pain management in the 1980s, approximately 80% of cancer patients achieve satisfactory pain relief by oral analgesic medications.5,6 However, the remaining 5% to 15% of advanced or terminal cancer patients do not achieve adequate pain improvement.6,7 Additionally, severe and intolerable side effects inevitably occur in patients along with an incremental application of oral analgesics.8 For these cancer patients with refractory pain or intolerable adverse events, advanced pain therapies are often required, including intrathecal drug delivery.9–11
Intrathecal analgesic delivery was first reported in 197912 and is increasingly used to control refractory pain in clinical practice. Analgesic medications are injected into the subarachnoid space through an intrathecal drug delivery system (IDDS), which produces better pain relief with smaller dosages than the traditional oral route.13–15 The advanced IDDS consists of a small, programmable pump that is wholly implanted beneath the skin of the abdomen and is attached to a catheter tunneled to the spinal entry site, such as the Medtronic SynchroMed II infusion system (Medtronic Inc., Minneapolis, MN, USA).16
At present, the site of the catheter tip is conventionally inserted in the subarachnoid space between the 8th and 10th thoracic vertebrae (T8, T10).7,9 Many intractable cancer pain patients achieve relief with conventional intrathecal therapy; however, most patients with primary or metastatic cancer in the middle thoracic vertebrae or above do not achieve sufficient pain relief.17 This unsatisfying analgesia may be related to blocked cerebral spinal fluid (CSF) circulation by tumor compression at higher level vertebrae. This challenge may be solved by placing the catheter tip in the intra-spinal space at a level above the upper cervical region.18 Theoretically, the location of pump catheter tip in the cisterna magna may provide better analgesic effects for these particular patients. In the present investigation, therefore, we performed a clinical trial to investigate the analgesic efficacy and safety of this new technique for pain relief in patients with advanced or terminal cancer at the middle thoracic vertebrae or above, and compared it with a conventional approach.
Methods
Participants
This was a prospective, non-randomized, multicenter clinical trial. Thirty-one patients suffering from intractable cancer-related pain were recruited from pain centers in two hospitals: Chinese People’s Liberation Army (PLA) General Hospital and the First Affiliated Hospital of Chinese Medical University. The study was approved by the Medical Ethics Committee of Chinese General Hospital of PLA (protocol ID: 200911087-01) and was registered in the Chinese Clinical Trial Registry (No. ChiCTR-ONN-17010681, http://www.chictr.org.cn). All participants provided written informed consent before the trial, and the study was performed in accordance with the Declaration of Helsinki. The patients were divided into 2 groups: a cisterna magna group receiving the intrathecal delivery to the cisterna magna and a conventional group receiving intrathecal delivery to the T8 to T10 levels. Participants in both two groups received an implantation of the Medtronic SynchroMed II device. The detailed group information was shown in Table 1.
Table 1. Group Information.
| Group (n) | Hospital | Location of catheter tip | IDDS | |||
| Cisterna magna group (n = 15) | Chinese PLA General Hospital | Cisterna magna | Medtronic SynchroMed II (Medtronic Inc., Minneapolis, MN, USA) | |||
| Conventional group (n = 15) | The First Affiliated Hospital of Chinese Medical University | From T8 to T10 | Medtronic SynchroMed II (Medtronic Inc., Minneapolis, MN, USA) |
T8: 8th thoracic vertebrae; T10: 10th thoracic vertebrae.
The patients were included according to the following criteria: (1) pain visual analogue scale (VAS) score persistently ⩾ 5; (2) unsatisfying analgesia with oral analgesics administration; (3) intolerable adverse events by oral analgesia; (4) life expectancy ⩾ 3 months; (5) a successful morphine trial. In addition to the above criteria,1–5 patients in the cisterna magna group also suffered from the primary or metastatic cancer at the middle thoracic vertebrae or above, and patients in the conventional group had the primary or metastatic cancer below the middle thoracic vertebrae.
The patients were excluded related to the following reasons: (1) allergy or adverse sensitivity to morphine; (2) serious coagulopathies, requiring anticoagulation therapy; (3) intracranial hypertension, sepsis or an infection at the site of the catheter or pump insertion; (4) severe mental disorders; (5) unable or unwilling to have the pump refilled; (6) drug abuse.
Baseline data were collected, including the demographic characteristics, primary cancer types, location of pain, location of metastasis, duration of hospitalization, and oral morphine or equivalent doses. In addition, pain VAS,7,19,20 the short form (36) health survey (SF-36)20,21 as well as the self-rating depression scale (SDS) scores22,23 were assessed and recorded before the catheter implantation.
Morphine Trial Protocol
An intrathecal trial was conducted prior to the implantation operation to identify eligible patients for IDDS administration.24 All opioids were discontinued for at least 12h before the trial. For the cisterna magna group patients, a spinal needle was inserted into the cisterna magna space under computed tomography (CT) guidance. For patients in the conventional group, the spinal needle was placed into the subarachnoid space at the L3 to L4 lumbar vertebrae level. Then, sterile saline containing morphine was immediately injected. Generally, the ratio of an intrathecal dose to an equivalent oral dose is 1:300, while the intrathecal dose at the level of cisterna magna is 2/3 of the dose injected at the L3 to L4 level. Each intrathecal trial was implemented with a single bolus injection for three consecutive days (once per day). A successful trial was considered as > 50% of pain relief, with few or no severe side effects. Patients with a successful intrathecal trial result continued to implantation of the IDDS.
Implantation of Morphine Pump in the Cisterna Magna
The implantation was performed in a sterile CT room. Patients were placed in the lateral position with their heads bent slightly forward. A small vertical incision was cut in the posterior cervical midline, approximate 2 inches below the incision. Under CT guidance, a 15-gauge spinal needle was punctured into the middle of cisterna magna space. After a free flow of CSF, the intrathecal catheter was inserted into the cisterna magna through the needle lumen. Next, the spinal needle was carefully removed. The catheter was then fixed at the position using an anchor in order to prevent catheter movement caused by frequent neck movement. A subcutaneous pocket with a depth < 2.5 cm was created in the abdomen and used as the morphine pump reservoir. The catheter was tunneled subcutaneously to the abdominal wall and connected to the pump, which was filled with 400 mg morphine. Eventually, the skin incision was securely closed by use of a sterile technique. The insertion process of a catheter tip into the cisterna magna space under CT guidance is shown in Figure 1.
Figure 1.
(A–I) The Insertion Process of The Catheter Tip into the Cisterna Magna Space Under The CT Guidance. (J–H) The Definite Location of the Implanted Catheter Tip Under the CT Guidance
CT: Computed Tomography.
Initially, the intrathecal morphine delivered into the cisterna magna was 20% of the intrathecal trial dose to reduce side effects. Then, dosing models of programmable pumps were modulated until pain was significantly improved (pain VAS score ⩽ 3). The optimal outpatient dosing was selected according to the individual demand to reach satisfactory pain relief.
Implantation of Morphine Pump in the Thoracic Region
The implantation was carried out in a sterile operating room. A lumbar puncture was conducted at the interspace between L3 and L4 using a 15-gauge spinal needle under the C-arm radiographic guidance. The intrathecal catheter was introduced through the spinal needle. Next, the catheter tip was securely inserted into the subarachnoid space from T8 to T10. After the fixation of the catheter, an abdominal pocket was created to place the SynchroMed II pump. Then, the catheter was tunneled subcutaneously to the anterior abdomen, and connected to the morphine pump. The pump was attached to the fascia, and the incision was closed in a sterile manner.
The initial dosing of intrathecal morphine administered into the subarachnoid space of the thoracic vertebrae was 20% of the trial dose to prevent potential adverse events. Then, dosing models of the programmable pump were adjusted until significant pain improvement was attained (pain VAS score ⩽ 3). The optimal outpatient dosing model was chosen according to the individual demand to achieve satisfactory pain relief.
Pain intensity Assessment
Pain intensity was assessed by using the VAS tool (a 0–10 continuous scale ranging from no pain to the worst pain imaginable) accomplished with the patients under the instruction of doctors. Successful pain improvement was defined as a VAS score ⩽ 3 in the present study.
Psychological Assessment
Patients’ quality of life were evaluated using the SF-36 tool, which consists of 8 dimensions, i.e., the physical function (PF), role physical (RP), body pain (BP), general health (GH), vitality (VT), social function (SF), role emotional (RE), mental health (MH) as well. The severity of depression was evaluated using the SDS.
Safety Assessment
To assess the safety, adverse events were monitored and recorded in detail after morphine pump implantation.
Post Procedure Follow Up
After receiving intrathecal therapy, there was long-term follow-up over 6 months for all patients. The follow-up was terminated related to removal of morphine pump or participant death. Pain VAS scores were assessed and recorded on the post-operative days 1, 7, 30, 90, and 180. SF-36 scores were evaluated and recorded on the post-operative days 7, 30, 90, and 180. SDS scores were evaluated and recorded on the post-operative day 1 and 7.
Statistical Analysis
Statistical analysis was performed using SPSS 20.0 software. The differences between the two groups were compared using the two-sample t test or the χ2 test. A p value < 0.05 was defined as statistical significance. The demographic features, the primary cancer types, pain locations, oral morphine or equivalent dose, pain VAS, SF-36 and SDS scores at baseline were analyzed and compared between the two groups. A Wilcoxon signed-rank test was conducted to compare the follow-up data with the baseline data.
RESULTS
Study Population
A total of 30 patients with refractory cancer pain received the intrathecal delivery and their data were collected and analyzed in the current study.
The demographic and clinical features were listed in Table 2. All demographic features were balanced between the two groups. For all patients, lung cancer (8/30) was the most common primary cancer type, followed by rectal cancer (4/30), liver cancer (3/30) and breast cancer (3/30). For patients in the cisterna magna, the location of pain was common in lumbar (15/15), chest (12/15) and abdomen (9/15), and for patients in the conventional group, the location of pain was common in the abdomen (9/15), lumbar (9/15) and chest (6/15). Before the intrathecal therapy, oral morphine or the equivalent dose in the cisterna magna group was significantly larger than the conventional group (470 ± 114 mg/24 h vs 262 ± 120 mg/24 h, P < 0.000). For patients in the cisterna magna group, baseline pain VAS score was significantly higher than the conventional group (7.8 ± 0.77 vs 16.7 ± 0.90, P = 0.001). For patients in the cisterna magna group, baseline GH score was significantly higher than the conventional group (20.7 ± 3.93 vs 16.0 ± 6.60, P = 0.001). The differences of baseline PF, RP, BP, VT, SF, RE, MH, as well as SDS scores were not different between the two groups.
Table 2. Patient Information.
| Characteristics | Cisterna magna group (n = 15) |
Conventional group (n = 15) |
P | |||
| Age, years | 57.2 ± 9.65 | 58.3 ± 10.94 | 0.766 | |||
| Gender (M/F) | 8/7 | 10/5 | 0.355 | |||
| Height, cm | 168.8 ± 7.28 | 171.2 ± 9.27 | 0.437 | |||
| Weight, kg | 62.2 ± 11.68 | 61.9 ± 10.68 | 0.936 | |||
| Education, n | 0.068 | |||||
| Less than primary school | 0 | 4 | ||||
| Middle school | 9 | 9 | ||||
| University | 6 | 2 | ||||
| Chronic disorders, n (Yes/No) | 4/11 | 7/8 | 0.225 | |||
| Type of primary cancer, n | ||||||
| Lung | 3 | 5 | ||||
| Rectal | 1 | 3 | ||||
| Liver | 2 | 1 | ||||
| Breast | 3 | 0 | ||||
| Cervical | 1 | 1 | ||||
| Prostate | 1 | 1 | ||||
| Stomach | 1 | 0 | ||||
| Gallbladder | 1 | 0 | ||||
| Ovarian | 1 | 0 | ||||
| Colon | 1 | 0 | ||||
| Pancreatic | 0 | 1 | ||||
| Endometrial | 0 | 1 | ||||
| Bladder | 0 | 1 | ||||
| Unknown cancer | 0 | 1 | ||||
| Location of pain, n | ||||||
| Back | 15 | 5 | ||||
| Chest | 12 | 6 | ||||
| Abdomen | 9 | 9 | ||||
| Lumbar | 4 | 9 | ||||
| Hip | 0 | 4 | ||||
| Sacrum | 0 | 4 | ||||
| Leg | 1 | 2 | ||||
| Neck | 2 | 0 | ||||
| Shoulder | 2 | 0 | ||||
| Perineum | 0 | 1 | ||||
| Location of metastasis, n | ||||||
| Above T7 | 15 | 0 | ||||
| Abdomen | 5 | 3 | ||||
| Pelvic cavity | 2 | 5 | ||||
| Liver | 3 | 3 | ||||
| Bone | 1 | 4 | ||||
| Lung | 1 | 4 | ||||
| Lumbar vertebrae | 0 | 2 | ||||
| Chest | 0 | 2 | ||||
| Whole body | 1 | 1 | ||||
| Duration of hospitalization, days | 15.2 ± 1.52 | 15.5 ± 6.83 | 0.885 | |||
| Oral morphine or equivalent dose, mg/24 h | 470 ± 114 | 262 ± 120 | < 0.000 | |||
| Baseline VAS score | 7.8 ± 0.77 | 6.7 ± 0.90 | 0.001 | |||
| Baseline SF-36 score | ||||||
| PF | 38.2 ± 8.39 | 39.3 ± 11.78 | 0.630 | |||
| RP | 29.1 ± 6.38 | 25.0 ± 13.39 | 0.618 | |||
| BP | 18.7 ± 3.03 | 20.4 ± 4.22 | 0.147 | |||
| GH | 20.7 ± 3.93 | 16.0 ± 6.60 | 0.001 | |||
| VT | 24.2 ± 5.32 | 23.3 ± 6.99 | 0.492 | |||
| SF | 27.9 ± 3.89 | 27.5 ± 7.01 | 0.770 | |||
| RE | 36.6 ± 7.28 | 38.4 ± 11.61 | 0.195 | |||
| MH | 31.0 ± 5.62 | 31.2 ± 7.1 | 0.897 | |||
| Baseline SDS score | 68.4 ± 2.38 | 65.8 ± 5.14 | 0.087 | |||
Continuous data were presented as meat ± standard derivation (SD).
M: male; F: female; T7: 7th thoracic vertebrae; VAS: visual analogue scale; SF-36: short form (36) health survey; PF: physical function; RP: role physical; BP: body pain; GH: general health; VT: vitality; SF: social function; RE: role emotional; MH: mental health; SDS: self-rating depression scale.
Pain Relief
Patients in both groups achieved satisfactory pain improvement with pain VAS score ⩽ 3. Although baseline VAS score was significantly higher in the cisterna magna group than that in the conventional group, pain VAS score in the cisterna magna group reduced to 3 or lower on post-operative day 1 (1.9 ± 0.80). In addition, successful pain relief was constantly observed during follow-up. In contrast, pain VAS score in the conventional group reduced to 3 or below on the post-operative day 7 (2.5 ± 1.25, Table S1). Compared with the conventional group, the decrease of pain VAS score in the cisterna magna group was more obvious on post-operative day 1 (74.9% ± 10.71% VS 47.4% ± 21.02%, P < 0.000) and 7 (76.6% ± 9.47% VS 63.2% ± 17.76%, P = 0.008), indicating that patients in the cisterna magna group attained better pain relief (Table S1 and Figure 2).
Table S1. The Post-Operative Follow-Up Visits.
| Pain relief (VAS) | Pain relief (VAS) | |||||||||||||||||||||
| Pain VAS score | Pain VAS score decrease (pre%) | |||||||||||||||||||||
| Baseline | Day 1 | Day 7 | Day 30 | Day 90 | Day 180 | Day 1 | Day 7 | Day 30 | Day 90 | Day 180 | ||||||||||||
| Cisterna magna group | 7.8 ± 0.77 | 1.9 ± 0.80 | 1.8 ± 0.68 | 2.3 ± 0.70 | 1.9 ± 0.76 | 2.3 ± 0.96 | 74.9% ± 10.71% | 76.6% ± 9.47% | 70.9% ± 9.06% | 76.4% ± 12.7% | 72.5% ± 10.25% | |||||||||||
| Conventional group | 6.7 ± 0.90 | 3.5 ± 1.55 | 2.5 ± 1.25 | 2.4 ± 0.96 | 2.5 ± 1.22 | 2.0 ± 1.73 | 47.4% ± 21.02% | 63.2% ± 17.76% | 69.3% ± 17.90% | 63.5% ± 15.70% | 69.8% ± 23.37% | |||||||||||
| P | 0.001 | 0.001 | 0.079 | 0.711 | 0.222 | 0.814 | 0.000 | 0.008 | 0.649 | 0.165 | 0.593 | |||||||||||
| Quality of life (SF-36) | Quality of life (SF-36) | |||||||||||||||||||||
| PF score | RP score | |||||||||||||||||||||
| Baseline | Day 7 | Day 30 | Day 90 | Day 180 | Baseline | Day 7 | Day 30 | Day 90 | Day 180 | |||||||||||||
| Cisterna magna group | 38.2 ± 8.39 | 49.9 ± 9.03 | 54.1 ± 7.71 | 52.8 ± 9.56 | 53.4 ± 3.13 | 29.1 ± 6.38 | 40.0 ± 8.31 | 46.5 ± 10.49 | 46.7 ± 12.01 | 51.2 ± 3.42 | ||||||||||||
| Conventional group | 39.3 ± 11.78 | 41.0 ± 11.83 | 46.5 ± 10.88 | 47.5 ± 14.64 | 53.3 ± 10.41 | 28.8 ± 9.39 | 30.8 ± 10.96 | 41.7 ± 12.31 | 42.9 ± 18.90 | 33.3 ±14.43 | ||||||||||||
| P | 0.630 | 0.002 | 0.002 | 0.076 | 0.748 | 0.618 | 0.000 | 0.000 | 0.233 | 0.155 | ||||||||||||
| BP score | GH score | |||||||||||||||||||||
| Baseline | Day 7 | Day 30 | Day 90 | Day 180 | Baseline | Day 7 | Day 30 | Day 90 | Day 180 | |||||||||||||
| Cisterna magna group | 18.7 ± 3.03 | 56.3 ± 7.94 | 61.7 ± 5.60 | 61.9 ± 4.56 | 62.6 ± 6.69 | 20.7 ± 3.94 | 27.9 ± 7.25 | 28.3 ± 8.75 | 27.7 ± 7.93 | 27.0 ± 4.30 | ||||||||||||
| Conventional group | 20.4 ± 4.22 | 51.2 ± 11.79 | 56.2 ± 7.19 | 54.6 ± 9.64 | 59.3 ± 6.43 | 16.0 ± 6.60 | 17.3 ± 5.94 | 21.2 ± 9.16 | 21.3 ± 7.44 | 20.0 ± 8.66 | ||||||||||||
| P | 0.147 | 0.016 | 0.032 | 0.023 | 0.053 | 0.001 | 0.000 | 0.003 | 0.155 | 0.492 | ||||||||||||
| VT score | SF score | |||||||||||||||||||||
| Baseline | Day 7 | Day 30 | Day 90 | Day 180 | Baseline | Day 7 | Day 30 | Day 90 | Day 180 | |||||||||||||
| Cisterna magna group | 24.3 ± 5.32 | 38.1 ± 5.40 | 41.2 ± 6.89 | 41.7 ± 7.24 | 42.8 ± 9.63 | 27.9 ± 3.90 | 46.9 ± 10.35 | 52.8 ± 8.51 | 51.1 ± 8.08 | 57.4 ± 5.77 | ||||||||||||
| Conventional group | 23.3 ± 6.99 | 28.7 ± 6.67 | 32.7 ± 9.49 | 35.0 ± 9.64 | 36.7 ± 10.41 | 27.5 ± 7.01 | 41.7 ± 12.20 | 47.1 ± 13.65 | 46.9 ± 12.94 | 54.2 ± 14.43 | ||||||||||||
| P | 0.492 | 0.000 | 0.000 | 0.002 | 0.112 | 0.770 | 0.071 | 0.061 | 0.032 | 0.393 | ||||||||||||
| RE score | MH score | |||||||||||||||||||||
| Baseline | Day 7 | Day 30 | Day 90 | Day 180 | Baseline | Day 7 | Day 30 | Day 90 | Day 180 | |||||||||||||
| Cisterna magna group | 36.7 ± 7.28 | 52.8 ± 7.52 | 59.3 ± 7.52 | 56.1 ± 6.80 | 55.0 ± 7.97 | 31.1 ± 5.62 | 51.3 ± 3.50 | 53.7 ± 5.15 | 52.0 ± 5.39 | 54.8 ± 7.19 | ||||||||||||
| Conventional group | 38.4 ± 11.61 | 45.0 ± 16.10 | 54.3 ± 16.71 | 38.1 ± 11.67 | 45.0 ± 19.05 | 31.2 ± 7.12 | 38.4 ± 6.38 | 40.3 ± 9.59 | 41.0 ± 9.97 | 41.3 ± 9.24 | ||||||||||||
| P | 0.195 | 0.010 | 0.176 | 0.000 | 0.196 | 0.897 | 0.000 | 0.000 | 0.004 | 0.082 | ||||||||||||
| Depression (SDS) | Depression (SDS) | |||||||||||||||||||||
| SDS score | SDS score decrease (pre%) | |||||||||||||||||||||
| Baseline | Day 7 | Day 30 | Day 7 | Day 30 | ||||||||||||||||||
| Cisterna magna group | 68.4 ± 2.38 | 52.3 ± 2.69 | 49.5 ± 4.73 | 23.5% ± 3.73% | 27.5% ± 7.21% | |||||||||||||||||
| Conventional group | 65.8 ± 5.14 | 62.6 ± 5.03 | 60.3 ± 4.37 | 4.9% ± 2.22% | 8.2% ± 2.82% | |||||||||||||||||
| P | 0.087 | 0.000 | 0.000 | 0.000 | 0.000 | |||||||||||||||||
Continuous data were presented as meat ± standard derivation (SD).
; VAS: visual analogue scale; SF-36: short form (36) health survey; PF: physical function; RP: role physical; BP: body pain; GH: general health; VT: vitality; SF: social function; RE: role emotional; MH: mental health; SDS: self-rating depression scale.
Figure 2.
The 6-Months Follow-Up Visits. (A) The Decrease of Pain VAS Scores Were Assessed and Compared Between the Cisterna Magna and Conventional Groups on the Post-Operative day 1, 7, 30, 90, and 180. The SF-36 Scores Were Assessed and Compared Between the Two Groups on the Post-Operative Day 7, 30, 90, and 180, Including (B) PF Scores, (C) RP Scores, (D) BP Scores, (E) GH Scores, (F) VT Scores, (G) SF Scores, (H) RE Scores, and (I) MH Scores. (J) The Decrease of SDS Scores Were Assessed and Compared Between the Cisterna Magna and Conventional Groups on the Post-Operative Day 1 and 7
VAS: visual analogue scale; SF-36: short form (36) health survey; PF: physical function; RP: role physical; BP: body pain; GH: general health; VT: vitality; SF: social function; RE: role emotional; MH: mental health; SDS: self-rating depression scale.
Quality of Life and Depression Assessment
Patient quality of life was improved after receiving intrathecal morphine delivery indicated as significant increase of SF-36 scores (Table S1 and Figure 2). Compared with the conventional group, patients in the cisterna magna group achieved better improvement in PF scores (day 7 and 30), RP scores (day 7 and 30), BP scores (day 7, 30 and 90), GH scores (day 7, 30 and 90), VT scores (day 7, 30 and 90), SF scores (day 90), RE scores (day 7 and 90), and MH scores (day 7, 30 and 90), shown in the Table S1 and Figure 2. In addition, patients in the cisterna magna group attained better improvement in depression with a significantly decreased SDS scores after the intrathecal morphine delivery, shown in Table S1 and Figure 2.
Adverse Events
Types of adverse events were different between the two groups. Delirium was commonly observed in the cisterna magna group after performing the morphine pump implantation operation, shown in the Table S2. In contrast, the occurrence of pharmacological side effects was increased in the conventional group, including the urinary retention (n = 5), headache (n = 2), dizziness (n = 2), hypotension (n = 1) and constipation (n = 1), shown in the Table S2. At the post-operative day 135, the morphine pump was removed from 1 patient in the conventional group due to the intolerable pain by movement.
Table S2. Adverse Events.
| Delirium | Urinary retention | Headache | Dizziness | Hypotension | Hyperidrosis | Constipation | ||||||||
| Cisterna magna group, n | 15 | 0 | 0 | 0 | 0 | 1 | 0 | |||||||
| Conventional group, n | 0 | 5 | 2 | 2 | 1 | 0 | 1 |
Discussion
The present investigation demonstrated that an intrathecal morphine pump implanted in the cisterna magna might be an effective as well as safe technique to control refractory cancer-related pain, particularly for specific patients suffering from advanced or terminal cancer at the middle thoracic vertebrae or above. Moreover, satisfying pain relief was achieved with intrathecal morphine delivery, which is consistent with previous studies.7,9,25,26 The novelty of the current study was the adoption of an advanced implantation technique, i.e., placing a catheter tip in the cisterna magna space. Compared with the conventional approach, greater pain improvement with a smaller morphine dose was shown in participants receiving the cisterna magna morphine delivery.
Several facts may contribute to the interpretation of these results: morphine receptors are distributed in the brain, especially in the periaqueductal gray region, amygdala, nucleus medialis thalami, and spinomesencephalic tract with high density.27,28 In order to reach an expected analgesia, a larger dose of morphine is used via intrathecal morphine delivery at lower thoracic or lumbar levels related to decreased intra-spinal morphine concentration from T12 to the cisterna magna (24% of T12).29 However, this new approach to date has been limited in clinical practices related to significant challenges in the implantation process. Cisterna magna is a relatively large space lying between the medulla oblongata and cerebellum30 and it is crucial and more convenient to collect CSF or perform intrathecal drug delivery compared to other cerebral regions above the cervical level.31 However, the long distance from skin to the cistern as well as the depth of cisterna magna varies among individuals with different gender, weight, or age.32 To greatly reduce the risk of brain injury, the catheter tip should be placed into the cisterna magna under CT guidance.
Quality of life is an essential indicator to evaluate the impact of disease or intervention on physiological, psychological and social activity.33 It is known that cancer-related pain, especially the intractable pain, may seriously impair the patients’ quality of life.34 In addition, most advanced or terminal cancer patients usually suffer from depression. Refractory pain, unsatisfactory pain relief, and intolerable side effects are the primary factors that finally give rise to the depression.33 Previous studies suggested that depression might seriously impair the therapeutic effects and reduce the quality of life of survived cancer patients.22,35 Prior to the implantation operation, participants with low SF-36 scores and high SDS scores in the study supported these facts.
While quality of life as well as depression of patients in the study were improved after receiving the intrathecal morphine delivery, indicating the clinical efficacy of intrathecal morphine pump therapy. In addition, patients receiving the cisterna magna intrathecal morphine delivery achieved greater improvement in quality of life as well as improved depression rate. This might be related to the fact that refractory cancer pain of patients with primary or metastatic cancer at the middle thoracic vertebrae or above was still a difficult problem to manage.17 These specific patients were more hopeless, while the quality of life as well as depression were likely significantly improved related to successful pain relief after receiving the cisterna magna morphine pump therapy.
Generally, common adverse events of intrathecal morphine pump therapy may be classified into four categories, i.e., surgical complications, mechanical system complications, drug-related side effects or refilling complications.16 For patients receiving the cisterna magna intrathecal morphine delivery, delirium was the most common complication. Post-operative delirium is an acute central nervous system dysfunction, manifesting as transient disturbance of consciousness, cognition, and perception.36 However, the mechanisms of post-operative delirium still remain unclear. Although the post-operative delirium may extend the hospital stay and increase medical costs,37 patients with delirium in the study completely recovered in two or three days after olanzapine administration. For patients in the conventional group, adverse events were primarily drug-related complications, involving urinary retention, headache, vertigo, and constipation. These adverse events were almost eliminated by reducing the intrathecal morphine dose or conventional treatment. In addition, severe adverse events were not observed in the present study, such as spinal cord compression, intrathecal infection, and respiratory depression.15,38
The study had several limitations. Related to selection bias by non-randomized design, although the accuracy of results might be questioned, it should be noted that based on medical literature, there has been no effective treatment for patients with primary or metastatic cancer at the middle thoracic vertebra or above to effectively control pain. In consideration of compliance of Medical Ethics, economics status and available medical resource, specific patients were identified as not suitable for accepting random intrathecal therapy.
Conclusions
In the present investigation, we have demonstrated that cisterna magna intrathecal morphine delivery might be an effective and safe technique for patients suffering from cancer at the middle thoracic vertebrae or above to control refractory cancer-related pain. However, larger sample sized, multicenter, prospective clinical study with more rigorous trial design need to be carried out to confirm our conclusions.
Declarations
Ethics Approval and Consent to Participate
The trial was conducted according to the principles of the declaration of Helsinki, and has been approved by the medical ethics committee of Chinese General Hospital of PLA (Medical Ethics Committee number 200911087-01) on November, 8rd, 2009. Written informed consent will be obtained from all patients or their close relatives before the trial.
Consent for Publication
Not applicable (this article does not contain any identifying data).
Availability of Data and Materials
The datasets and/or analyzed data will be available from the corresponding author on reasonable request. Only researchers who need access to all data, when collecting or analyzing data, and the principal investigator have access to all data.
Competing Interests
All authors declare that they have no competing interests. Drs. Sun C Wang YT and Dia YJ contributed equally to this project.
Funding
This study was sponsored by a grant of the Science and Technology Development of Medicine from Ministry of Health of the People’s Republic of China (W2013ZT002 to Prof. Sun YH), Science and Technique Development Grant of Shaanxi Province (2012K18-01-08 to Mrs. Sun LL; 2015SF179 to Dr. Wang YT) and Science&Technique Founding of Xijing Hospital (XJZT18ML59 to Mrs. Sun LL). The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Authors, Contributions
All authors contributed to the design of the study protocol. YHS, ADK, TS, YJ and LLS conceived the study design in several meetings. CS, YTW and YJD wrote the initial draft of the manuscript and gave final approval of the version to be published. JY, DSD, CFW, GLZ, GJL, ZQC, ADK, OV, IU, and ZHL critically reviewed and provided constructive comments to it. All authors read and approved the final manuscript.
Acknowledgments
We would like to thank the staff involved in this study from the Chinese General Hospital of PLA and the First Affiliated Hospital of China Medical University, for their help in recruiting study participants and to the study participants that participated in the data collection. We also acknowledge the contribution of Medjaden Bioscience Limited, for the final editorial revision of this manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets and/or analyzed data will be available from the corresponding author on reasonable request. Only researchers who need access to all data, when collecting or analyzing data, and the principal investigator have access to all data.